Serum lipid antibodies are associated with cerebral tissue damage in multiple sclerosis The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Bakshi, R., A. Yeste, B. Patel, S. Tauhid, S. Tummala, R. Rahbari, R. Chu, et al. 2016. Serum Lipid Antibodies Are Associated with Cerebral Tissue Damage in Multiple Sclerosis. Neurology: Neuroimmunology & Neuroinflammation 3, no. 2: e200–e200. doi:10.1212/nxi.0000000000000200. Published Version doi:10.1212/nxi.0000000000000200 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:25918568 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA
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Serum lipid antibodies areassociated with cerebral tissue
damage in multiple sclerosisThe Harvard community has made this
article openly available Please share howthis access benefits you Your story matters
Citation Bakshi R A Yeste B Patel S Tauhid S Tummala R RahbariR Chu et al 2016 Serum Lipid Antibodies Are Associatedwith Cerebral Tissue Damage in Multiple Sclerosis NeurologyNeuroimmunology amp Neuroinflammation 3 no 2 e200ndashe200doi101212nxi0000000000000200
Published Version doi101212nxi0000000000000200
Citable link httpnrsharvardeduurn-3HULInstRepos25918568
Terms of Use This article was downloaded from Harvard Universityrsquos DASHrepository and is made available under the terms and conditionsapplicable to Other Posted Material as set forth at httpnrsharvardeduurn-3HULInstReposdashcurrentterms-of-useLAA
Serum lipid antibodies are associated withcerebral tissue damage in multiple sclerosis
ABSTRACT
Objective To determine whether peripheral immune responses as measured by serum antigenarrays are linked to cerebral MRI measures of disease severity in multiple sclerosis (MS)
Methods In this cross-sectional study serum samples were obtained from patients withrelapsing-remitting MS (n 5 21) and assayed using antigen arrays that contained 420 antigensincluding CNS-related autoantigens lipids and heat shock proteins Normalized compartment-specific global brain volumes were obtained from 3-tesla MRI as surrogates of atrophy includinggray matter fraction (GMF) white matter fraction (WMF) and total brain parenchymal fraction(BPF) Total brain T2 hyperintense lesion volume (T2LV) was quantified from fluid-attenuatedinversion recovery images
Results We found serum antibody patterns uniquely correlated with BPF GMF WMF and T2LVFurthermore we identified immune signatures linked to MRI markers of neurodegeneration (BPFGMF WMF) that differentiated those linked to T2LV Each MRI measure was correlated with aspecific set of antibodies Strikingly immunoglobulin G (IgG) antibodies to lipids were linked tobrain MRI measures Based on the association between IgG antibody reactivity and each uniqueMRI measure we developed a lipid index This comprised the reactivity directed against all of thelipids associated with each specific MRI measure We validated these findings in an additionalindependent set of patients with MS (n 5 14) and detected a similar trend for the correlationsbetween BPF GMF and T2LV vs their respective lipid indexes
Conclusions We propose serum antibody repertoires that are associated with MRI measuresof cerebral MS involvement Such antibodies may serve as biomarkers for monitoring diseasepathology and progression Neurol Neuroimmunol Neuroinflamm 20163e200 doi 101212
NXI0000000000000200
GLOSSARYBPF 5 brain parenchymal fraction GM 5 gray matter GMF 5 gray matter fraction IgG 5 immunoglobulin G MS 5 multiplesclerosis T2LV 5 T2 hyperintense lesion volume WM 5 white matter WMF 5 white matter fraction
Multiple sclerosis (MS) is characterized by immune dysfunction and inflammation leading tofocal lesions brain and spinal cord atrophy and progressive neurologic dysfunction The knownheterogeneity likely reflects myriad and complex underlying pathogenic mechanisms that makespecific and unique contributions to MS1
MRI-defined T2 hyperintense brain lesions are key to diagnosis and therapeutic monitoringHowever such lesions are nonspecific for the underlying pathology and have limited clinicalpredictive value23 Measurement of brain atrophy provides the potential to detect destructivedisease effects and show better associations with clinical status than can be obtained with lesionmeasures2 Atrophy begins early in MS and can be monitored by MRI segmentation2ndash4 Graymatter (GM) atrophy is more closely linked to clinical status than white matter (WM) atrophy
From the Partners Multiple Sclerosis Center (RB S Tauhid S Tummala RC HLW) and Ann Romney Center for Neurologic Diseases (RBAY BP RR KR PK HLW FJQ) Neurology (RB AY BP S Tauhid S Tummala RR RC KR PK HLW FJQ) andRadiology (RB) Brigham and Womenrsquos Hospital Harvard Medical School Boston MA
Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was paid by the authors
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially
Neurologyorgnn copy 2016 American Academy of Neurology 1
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
whole brain atrophy or conventional lesionassessments56 This likely reflects the func-tional importance of GM and the contentionthat pseudoatrophy confounds the use ofwhole brain or WM atrophy to monitor pro-gressive neurodegeneration7
Immune processes have a central role inboth the pathogenesis and treatment ofMS8ndash12 The ability to link such changes toMRI presents the opportunity to providenew biomarkers and better understanding ofdisease pathophysiology13ndash19
Antigen microarrays are newly developedtools for the high-throughput characterizationof the immune response2021 that have beenused to identify biomarkers and mechanismsof disease pathogenesis in several autoimmunedisorders including MS22ndash31 In the presentstudy we investigated the relationship betweenantigen arrays and both GM and WM cerebralMRI involvement in MS
METHODS Patients Table 1 summarizes the patientsrsquo
demographic and clinical characteristics of the discovery and val-
idation sets All serum samples were collected from the ongoing
cohort of patients being followed in the CLIMB study (Compre-
hensive Longitudinal Investigation of MS at Brigham and
Womenrsquos Hospital32) in which participants are followed with
comprehensive clinical and imaging assessments to monitor
disease progression and response to therapy on a yearly basis
Samples were collected within (mean 6 SD) 50 6 32 months
of MRI acquisition Patients were free of relapses or changes in
disease-modifying therapy during the interval between blood
collection and MRI This was a consecutive sample meeting the
following criteria (1) age 18 to 55 years (2) diagnosis of
relapsing-remitting MS33 (3) absence of other major medical
neurologic or neuropsychiatric disorders (4) lack of any relapse
or corticosteroid use in the 4 weeks before MRI or start of disease-
modifying therapy 6 months before MRI (to reduce confounding
effects on MRI) and (5) no history of smoking or substance
abuse The majority of patients were receiving disease-
modifying treatment at the time of MRI Within 3 months of
MRI each patient received an examination by an MS specialist-
neurologist including evaluation of neurologic disability on the
Expanded Disability Status Scale and a timed 25-foot walk
Standard protocol approvals registrations and patientconsents Our study received approval from the ethical standards
committee on human experimentation at our institution
(The Partners Health Care Institutional Review Board) All par-
ticipants gave written informed consent for their participation in
the study
MRI acquisition and analysis All participants in the discoveryset underwentMRI on the same scanner (3T Signa General Electric
Healthcare Milwaukee WI) using a receive-only phase array head
coil with the same MRI protocol The scan acquisition protocol
has been detailed previously34 Contiguous slices covering the
whole brain were acquired in high-resolution protocols using
3-dimensional modified driven equilibrium Fourier transform and
T2-weighted fast fluid-attenuated inversion recovery sequences
Patients in the validation set underwent brain MRI on a 15T
scanner (GE Signa) including a 2-dimensional axial conventional
spin-echo dual-echo T2-weighted series (voxel sizes 0943 0943
3 mm) Analysis of these scans was performed by operators who
were unaware of clinical and biomarker information In the
discovery set we obtained normalized compartment-specific
global brain volumes as surrogates of atrophy including GM
fraction (GMF) WM fraction (WMF) and total brain
parenchymal fraction (BPF) using statistical parametric mapping
version 8 (WellcomeDepartment of Cognitive Neurology London
UK httpwwwfilionuclacukspm) after manual correction of
(1) misclassifications of tissue compartments due to MS lesion and
(2) ineffective contouring of the deep GM structures34 In the
validation set BPF and GMF were obtained in statistical
parametric mapping version 8 from the dual-echo images
Because the source images did not show effective contrast for
segmentation of the deep gray structures we performed manual
masking to derive only the cerebral cortical GMF Quantification
of total brain T2 hyperintense lesion volume (T2LV) was performed
using Jim (Xinapse Systems Ltd West Bergholt UK httpwww
xinapsecom) by the consensus of 2 experienced observers from the
fluid-attenuated inversion recovery (discovery set) or dual-echo
(validation set) images using a semiautomated technique For the
measurement of these atrophy and lesion surrogates from MRI
scans our methods are well established regarding their operational
procedures validity and reliability34ndash39
Antigens Peptides were synthesized at the Biopolymers Facility
of the Department of Biological Chemistry and Molecular Phar-
macology of Harvard Medical School Recombinant proteins and
lipids were purchased from Sigma (St Louis MO) Abnova
(Taipei City Taiwan) Matreya LLC (Pleasant Gap PA) Avanti
Polar Lipids (Alabaster AL) Calbiochem (San Diego CA)
Chemicon (Temecula CA) GeneTex (San Antonio TX) Novus
Table 1 Demographic clinical and brain MRI data
Discovery seta Validation setb
No of patients with relapsing-remitting MS 21 14
Age y 406 6 80 471 6 81
Women n () 14 (67) 13 (93)
Disease duration y 68 6 50 127 6 81
EDSS score 14 6 12 17 6 19
Timed 25-ft walk s 47 6 06 83 6 102
BPFc 083 6 004 076 6 005
GMFc 049 6 004d 033 6 003e
WMF 033 6 002 NP
T2LVc mL 143 6 169 49 6 79
Abbreviations BPF 5 whole brain parenchymal fraction EDSS 5 Expanded Disability Sta-tus Scale GMF 5 cerebral gray matter fraction MS 5 multiple sclerosis NP 5 not per-formed T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral whitematter fractionValues represent mean 6 SD unless otherwise indicateda Fluid-attenuated inversion recovery 3T high resolutionbDual-echo 15T low resolutionc The 2 groups had different MRI acquisitionsource images (3T high resolution vs 15T lowresolution) and different software analysis pipelines leading to a difference in scalingbetween the MRI output metrics (see the methods section for more details)dWhole brain GMFeCortical GMF
2 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Table 2 Serum immunoglobulin Gs associated with MRI measures of disease severity
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Serum lipid antibodies are associated withcerebral tissue damage in multiple sclerosis
ABSTRACT
Objective To determine whether peripheral immune responses as measured by serum antigenarrays are linked to cerebral MRI measures of disease severity in multiple sclerosis (MS)
Methods In this cross-sectional study serum samples were obtained from patients withrelapsing-remitting MS (n 5 21) and assayed using antigen arrays that contained 420 antigensincluding CNS-related autoantigens lipids and heat shock proteins Normalized compartment-specific global brain volumes were obtained from 3-tesla MRI as surrogates of atrophy includinggray matter fraction (GMF) white matter fraction (WMF) and total brain parenchymal fraction(BPF) Total brain T2 hyperintense lesion volume (T2LV) was quantified from fluid-attenuatedinversion recovery images
Results We found serum antibody patterns uniquely correlated with BPF GMF WMF and T2LVFurthermore we identified immune signatures linked to MRI markers of neurodegeneration (BPFGMF WMF) that differentiated those linked to T2LV Each MRI measure was correlated with aspecific set of antibodies Strikingly immunoglobulin G (IgG) antibodies to lipids were linked tobrain MRI measures Based on the association between IgG antibody reactivity and each uniqueMRI measure we developed a lipid index This comprised the reactivity directed against all of thelipids associated with each specific MRI measure We validated these findings in an additionalindependent set of patients with MS (n 5 14) and detected a similar trend for the correlationsbetween BPF GMF and T2LV vs their respective lipid indexes
Conclusions We propose serum antibody repertoires that are associated with MRI measuresof cerebral MS involvement Such antibodies may serve as biomarkers for monitoring diseasepathology and progression Neurol Neuroimmunol Neuroinflamm 20163e200 doi 101212
NXI0000000000000200
GLOSSARYBPF 5 brain parenchymal fraction GM 5 gray matter GMF 5 gray matter fraction IgG 5 immunoglobulin G MS 5 multiplesclerosis T2LV 5 T2 hyperintense lesion volume WM 5 white matter WMF 5 white matter fraction
Multiple sclerosis (MS) is characterized by immune dysfunction and inflammation leading tofocal lesions brain and spinal cord atrophy and progressive neurologic dysfunction The knownheterogeneity likely reflects myriad and complex underlying pathogenic mechanisms that makespecific and unique contributions to MS1
MRI-defined T2 hyperintense brain lesions are key to diagnosis and therapeutic monitoringHowever such lesions are nonspecific for the underlying pathology and have limited clinicalpredictive value23 Measurement of brain atrophy provides the potential to detect destructivedisease effects and show better associations with clinical status than can be obtained with lesionmeasures2 Atrophy begins early in MS and can be monitored by MRI segmentation2ndash4 Graymatter (GM) atrophy is more closely linked to clinical status than white matter (WM) atrophy
From the Partners Multiple Sclerosis Center (RB S Tauhid S Tummala RC HLW) and Ann Romney Center for Neurologic Diseases (RBAY BP RR KR PK HLW FJQ) Neurology (RB AY BP S Tauhid S Tummala RR RC KR PK HLW FJQ) andRadiology (RB) Brigham and Womenrsquos Hospital Harvard Medical School Boston MA
Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was paid by the authors
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially
Neurologyorgnn copy 2016 American Academy of Neurology 1
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
whole brain atrophy or conventional lesionassessments56 This likely reflects the func-tional importance of GM and the contentionthat pseudoatrophy confounds the use ofwhole brain or WM atrophy to monitor pro-gressive neurodegeneration7
Immune processes have a central role inboth the pathogenesis and treatment ofMS8ndash12 The ability to link such changes toMRI presents the opportunity to providenew biomarkers and better understanding ofdisease pathophysiology13ndash19
Antigen microarrays are newly developedtools for the high-throughput characterizationof the immune response2021 that have beenused to identify biomarkers and mechanismsof disease pathogenesis in several autoimmunedisorders including MS22ndash31 In the presentstudy we investigated the relationship betweenantigen arrays and both GM and WM cerebralMRI involvement in MS
METHODS Patients Table 1 summarizes the patientsrsquo
demographic and clinical characteristics of the discovery and val-
idation sets All serum samples were collected from the ongoing
cohort of patients being followed in the CLIMB study (Compre-
hensive Longitudinal Investigation of MS at Brigham and
Womenrsquos Hospital32) in which participants are followed with
comprehensive clinical and imaging assessments to monitor
disease progression and response to therapy on a yearly basis
Samples were collected within (mean 6 SD) 50 6 32 months
of MRI acquisition Patients were free of relapses or changes in
disease-modifying therapy during the interval between blood
collection and MRI This was a consecutive sample meeting the
following criteria (1) age 18 to 55 years (2) diagnosis of
relapsing-remitting MS33 (3) absence of other major medical
neurologic or neuropsychiatric disorders (4) lack of any relapse
or corticosteroid use in the 4 weeks before MRI or start of disease-
modifying therapy 6 months before MRI (to reduce confounding
effects on MRI) and (5) no history of smoking or substance
abuse The majority of patients were receiving disease-
modifying treatment at the time of MRI Within 3 months of
MRI each patient received an examination by an MS specialist-
neurologist including evaluation of neurologic disability on the
Expanded Disability Status Scale and a timed 25-foot walk
Standard protocol approvals registrations and patientconsents Our study received approval from the ethical standards
committee on human experimentation at our institution
(The Partners Health Care Institutional Review Board) All par-
ticipants gave written informed consent for their participation in
the study
MRI acquisition and analysis All participants in the discoveryset underwentMRI on the same scanner (3T Signa General Electric
Healthcare Milwaukee WI) using a receive-only phase array head
coil with the same MRI protocol The scan acquisition protocol
has been detailed previously34 Contiguous slices covering the
whole brain were acquired in high-resolution protocols using
3-dimensional modified driven equilibrium Fourier transform and
T2-weighted fast fluid-attenuated inversion recovery sequences
Patients in the validation set underwent brain MRI on a 15T
scanner (GE Signa) including a 2-dimensional axial conventional
spin-echo dual-echo T2-weighted series (voxel sizes 0943 0943
3 mm) Analysis of these scans was performed by operators who
were unaware of clinical and biomarker information In the
discovery set we obtained normalized compartment-specific
global brain volumes as surrogates of atrophy including GM
fraction (GMF) WM fraction (WMF) and total brain
parenchymal fraction (BPF) using statistical parametric mapping
version 8 (WellcomeDepartment of Cognitive Neurology London
UK httpwwwfilionuclacukspm) after manual correction of
(1) misclassifications of tissue compartments due to MS lesion and
(2) ineffective contouring of the deep GM structures34 In the
validation set BPF and GMF were obtained in statistical
parametric mapping version 8 from the dual-echo images
Because the source images did not show effective contrast for
segmentation of the deep gray structures we performed manual
masking to derive only the cerebral cortical GMF Quantification
of total brain T2 hyperintense lesion volume (T2LV) was performed
using Jim (Xinapse Systems Ltd West Bergholt UK httpwww
xinapsecom) by the consensus of 2 experienced observers from the
fluid-attenuated inversion recovery (discovery set) or dual-echo
(validation set) images using a semiautomated technique For the
measurement of these atrophy and lesion surrogates from MRI
scans our methods are well established regarding their operational
procedures validity and reliability34ndash39
Antigens Peptides were synthesized at the Biopolymers Facility
of the Department of Biological Chemistry and Molecular Phar-
macology of Harvard Medical School Recombinant proteins and
lipids were purchased from Sigma (St Louis MO) Abnova
(Taipei City Taiwan) Matreya LLC (Pleasant Gap PA) Avanti
Polar Lipids (Alabaster AL) Calbiochem (San Diego CA)
Chemicon (Temecula CA) GeneTex (San Antonio TX) Novus
Table 1 Demographic clinical and brain MRI data
Discovery seta Validation setb
No of patients with relapsing-remitting MS 21 14
Age y 406 6 80 471 6 81
Women n () 14 (67) 13 (93)
Disease duration y 68 6 50 127 6 81
EDSS score 14 6 12 17 6 19
Timed 25-ft walk s 47 6 06 83 6 102
BPFc 083 6 004 076 6 005
GMFc 049 6 004d 033 6 003e
WMF 033 6 002 NP
T2LVc mL 143 6 169 49 6 79
Abbreviations BPF 5 whole brain parenchymal fraction EDSS 5 Expanded Disability Sta-tus Scale GMF 5 cerebral gray matter fraction MS 5 multiple sclerosis NP 5 not per-formed T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral whitematter fractionValues represent mean 6 SD unless otherwise indicateda Fluid-attenuated inversion recovery 3T high resolutionbDual-echo 15T low resolutionc The 2 groups had different MRI acquisitionsource images (3T high resolution vs 15T lowresolution) and different software analysis pipelines leading to a difference in scalingbetween the MRI output metrics (see the methods section for more details)dWhole brain GMFeCortical GMF
2 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Table 2 Serum immunoglobulin Gs associated with MRI measures of disease severity
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
whole brain atrophy or conventional lesionassessments56 This likely reflects the func-tional importance of GM and the contentionthat pseudoatrophy confounds the use ofwhole brain or WM atrophy to monitor pro-gressive neurodegeneration7
Immune processes have a central role inboth the pathogenesis and treatment ofMS8ndash12 The ability to link such changes toMRI presents the opportunity to providenew biomarkers and better understanding ofdisease pathophysiology13ndash19
Antigen microarrays are newly developedtools for the high-throughput characterizationof the immune response2021 that have beenused to identify biomarkers and mechanismsof disease pathogenesis in several autoimmunedisorders including MS22ndash31 In the presentstudy we investigated the relationship betweenantigen arrays and both GM and WM cerebralMRI involvement in MS
METHODS Patients Table 1 summarizes the patientsrsquo
demographic and clinical characteristics of the discovery and val-
idation sets All serum samples were collected from the ongoing
cohort of patients being followed in the CLIMB study (Compre-
hensive Longitudinal Investigation of MS at Brigham and
Womenrsquos Hospital32) in which participants are followed with
comprehensive clinical and imaging assessments to monitor
disease progression and response to therapy on a yearly basis
Samples were collected within (mean 6 SD) 50 6 32 months
of MRI acquisition Patients were free of relapses or changes in
disease-modifying therapy during the interval between blood
collection and MRI This was a consecutive sample meeting the
following criteria (1) age 18 to 55 years (2) diagnosis of
relapsing-remitting MS33 (3) absence of other major medical
neurologic or neuropsychiatric disorders (4) lack of any relapse
or corticosteroid use in the 4 weeks before MRI or start of disease-
modifying therapy 6 months before MRI (to reduce confounding
effects on MRI) and (5) no history of smoking or substance
abuse The majority of patients were receiving disease-
modifying treatment at the time of MRI Within 3 months of
MRI each patient received an examination by an MS specialist-
neurologist including evaluation of neurologic disability on the
Expanded Disability Status Scale and a timed 25-foot walk
Standard protocol approvals registrations and patientconsents Our study received approval from the ethical standards
committee on human experimentation at our institution
(The Partners Health Care Institutional Review Board) All par-
ticipants gave written informed consent for their participation in
the study
MRI acquisition and analysis All participants in the discoveryset underwentMRI on the same scanner (3T Signa General Electric
Healthcare Milwaukee WI) using a receive-only phase array head
coil with the same MRI protocol The scan acquisition protocol
has been detailed previously34 Contiguous slices covering the
whole brain were acquired in high-resolution protocols using
3-dimensional modified driven equilibrium Fourier transform and
T2-weighted fast fluid-attenuated inversion recovery sequences
Patients in the validation set underwent brain MRI on a 15T
scanner (GE Signa) including a 2-dimensional axial conventional
spin-echo dual-echo T2-weighted series (voxel sizes 0943 0943
3 mm) Analysis of these scans was performed by operators who
were unaware of clinical and biomarker information In the
discovery set we obtained normalized compartment-specific
global brain volumes as surrogates of atrophy including GM
fraction (GMF) WM fraction (WMF) and total brain
parenchymal fraction (BPF) using statistical parametric mapping
version 8 (WellcomeDepartment of Cognitive Neurology London
UK httpwwwfilionuclacukspm) after manual correction of
(1) misclassifications of tissue compartments due to MS lesion and
(2) ineffective contouring of the deep GM structures34 In the
validation set BPF and GMF were obtained in statistical
parametric mapping version 8 from the dual-echo images
Because the source images did not show effective contrast for
segmentation of the deep gray structures we performed manual
masking to derive only the cerebral cortical GMF Quantification
of total brain T2 hyperintense lesion volume (T2LV) was performed
using Jim (Xinapse Systems Ltd West Bergholt UK httpwww
xinapsecom) by the consensus of 2 experienced observers from the
fluid-attenuated inversion recovery (discovery set) or dual-echo
(validation set) images using a semiautomated technique For the
measurement of these atrophy and lesion surrogates from MRI
scans our methods are well established regarding their operational
procedures validity and reliability34ndash39
Antigens Peptides were synthesized at the Biopolymers Facility
of the Department of Biological Chemistry and Molecular Phar-
macology of Harvard Medical School Recombinant proteins and
lipids were purchased from Sigma (St Louis MO) Abnova
(Taipei City Taiwan) Matreya LLC (Pleasant Gap PA) Avanti
Polar Lipids (Alabaster AL) Calbiochem (San Diego CA)
Chemicon (Temecula CA) GeneTex (San Antonio TX) Novus
Table 1 Demographic clinical and brain MRI data
Discovery seta Validation setb
No of patients with relapsing-remitting MS 21 14
Age y 406 6 80 471 6 81
Women n () 14 (67) 13 (93)
Disease duration y 68 6 50 127 6 81
EDSS score 14 6 12 17 6 19
Timed 25-ft walk s 47 6 06 83 6 102
BPFc 083 6 004 076 6 005
GMFc 049 6 004d 033 6 003e
WMF 033 6 002 NP
T2LVc mL 143 6 169 49 6 79
Abbreviations BPF 5 whole brain parenchymal fraction EDSS 5 Expanded Disability Sta-tus Scale GMF 5 cerebral gray matter fraction MS 5 multiple sclerosis NP 5 not per-formed T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral whitematter fractionValues represent mean 6 SD unless otherwise indicateda Fluid-attenuated inversion recovery 3T high resolutionbDual-echo 15T low resolutionc The 2 groups had different MRI acquisitionsource images (3T high resolution vs 15T lowresolution) and different software analysis pipelines leading to a difference in scalingbetween the MRI output metrics (see the methods section for more details)dWhole brain GMFeCortical GMF
2 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Table 2 Serum immunoglobulin Gs associated with MRI measures of disease severity
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
Table 2 Serum immunoglobulin Gs associated with MRI measures of disease severity
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Sci Inc (Poway CA) EMD Biosciences (San Diego CA) Cay-
man Chemical (Ann Arbor MI) HyTest (Turku Finland)
Meridian Life Science (Memphis TN) and Biodesign Interna-
tional (Saco ME) The antigens used in the construction of anti-
gen microarrays are listed in table e-1 at Neurologyorgnn
Antigen microarray production development and dataanalysis The antigens listed in table e-1 were spotted in replicatesof 6 on SuperEpoxy 2 slides (TeleChem Sunnyvale CA) using
an Arrayit NanoPrint 2 LM210 microarray printer (Arrayit Corpo-
ration Sunnyvale CA) and optimized spotting conditions as
described28303140 The microarrays were hybridized using an HS
4800Pro Hybridization Station (Tecan Maumlnnedorf Switzerland)
in which they were blocked with 1 bovine serum albumin for
1 hour and incubated for 2 hours at 37degC with the test serum at
a 1100 dilution in blocking buffer The arrays were then washed
and incubated for 45 minutes with a 1500 dilution of goat
anti-human immunoglobulin G (IgG) Cy3-conjugated and
ImmunoResearch Labs West Grove PA) The arrays were scanned
with a Tecan PowerScanner Repeated measurements indicate that
our antigen microarray technique is reproducible exhibiting
a coefficient of variation of 1336 1231
Background signal was subtracted and raw data were normal-
ized and analyzed using the GeneSpring software (Silicon Genetics
Redwood City CA) Antigen reactivity was defined by the mean
intensity of binding to the replicates of that antigen on the micro-
array and expressed as relative fluorescence units Scatter plots were
generated using linear regression models in the R statistical package
Pearson product-moment correlation coefficients were calculated
between the MRI measures (BPF GMF WMF T2LV) and the
weighted average of a group of statistically significant lipids The
weighted average of significant lipids was calculated using the for-
mula (SWiAiSWi) (SWi 5 1 i 5 1 2 3 ) where Wi is the
proportion of intensity of antigen Ai Ai is the observed intensity of
an antigen and SWi is the sum of the weights
RESULTS Serum IgG antibodies correlate with brain
MRI measures of disease severity To study the relation-ship between the peripheral immune response andMRI measures of disease severity we analyzed serum
antibody reactivity in those MS samples We analyzedIgG serum antibodies using a panel of antigensincluding CNS antigens heat shock proteins and lip-ids The association between the antibody reactivityagainst each antigen and 4 MRI measures of disease(T2LV BPF WMF and GMF) was investigatedusing Spearman correlation tests
We found significant associations between eachMRI measure of disease and different sets of IgG anti-body reactivity which are shown in table 2 Similarpatterns of antibody reactivity were linked to BPFand GMF consistent with the known dominant con-tribution of GM atrophy to whole brain atrophymeasures3741 Strikingly there was little overlapbetween the antibody reactivity associated withGMF and WMF suggesting that different immuno-pathologic processes contribute to tissue degenerationin these areas of the brain Similarly these profiles ofantibody reactivity were also different from thoseassociated with T2LV
Serum lipid-reactive IgGs are associated with increased
disease pathogenesis determined by MRI In evaluationof MRI measures and their link to disease BPFGMF and WMF decrease with disease progressionwhile T2LV increases with disease progressionAccordingly we analyzed the linkage between eachMRI measure and the significant antibody reactivitiesshown in table 2 We identified IgG antibody reac-tivities associated with increased tissue destruction asevidenced by decreased BPF values (figure 1) Strik-ingly we found that antibodies linked to diseasepathology as measured by BPF were enriched for reac-tivity against lipids Furthermore a selective increasein lipid-reactive antibodies linked to disease severitywas also observed when we analyzed all available MRImeasures (figure 2) Of note we did not detect an
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
enrichment in lipid-reactive IgM in the group ofantibodies associated with increased diseasepathogenesis (not shown)
An index of serum IgG reactivity to lipids is associated
with MRI measures of disease severity To further inves-tigate the association between serum IgG reactivityto lipids and MRI measures of disease severity wecalculated an IgG anti-lipid index for each patientcorresponding to the information on each lipid-specific antibody listed in table 2 normalized by thestrength of its correlation with that MRI measureunder investigation The antibody reactivities tolipids used to calculate the lipid index are shown in
figure 3A With this approach we calculated one indexfor each of the MRI measures analyzed in this studyWe found a significant correlation between each IgGlipid antibody index and BPF GMF and T2LV(figure 3B) no significant correlation was found withWMF Moreover no significant correlations werefound between BPF WMF GMF and T2LVmeasures and anti-lipid antibody indexes based onIgM reactivity (not shown)
Finally we evaluated the performance of the lipidantibody indexes linked to BPF GMF and T2LV onan additional set of independent MS samples (valida-tion set table 1) We detected a similar trend to theone detected in the discovery set with regard to the
Figure 1 Antibody reactivity in serum is associated with decreased brain volume
Heatmap in which each column represents the mean immunoglobulin G antibody reactivity in a serum sample from a patient with multiple sclerosis sortedaccording to the whole brain parenchymal fraction (BPF) (indicated at the topmdasha lower BPF indicates more brain atrophy) and each row represents theantibody reactivity to an antigen according to the colorimetric scale shown The antibody reactivities included in this heatmap are listed in table 2
6 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
Figure 2 Association of serum IgG reactivity with MRI measures of disease severity
(A) Heatmap in which each column represents an MRI measure of either atrophy (BPF GMF WMF) or lesions (T2LV) andeach row represents the correlation to IgG serum antibody reactivity according to a colorimetric scale (B) Frequency oflipid-reactive antibodies linked to higher or lower MRI disease severity BPF 5 whole brain parenchymal fraction GMF 5
global cerebral gray matter fraction IgG 5 immunoglobulin G T2LV 5 cerebral T2 (fluid-attenuated inversion recovery)hyperintense lesion volume WMF 5 global cerebral white matter fraction
Neurology Neuroimmunology amp Neuroinflammation 7
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
correlation between BPF and GMF and their respec-tive lipid indexes and we validated the correlationbetween T2LV and its lipid index (figure 3C)
DISCUSSION Previous studies have investigated theassociation of MRI with immune activity in MS13ndash19
These studies have included cellular immune measures
Figure 3 Correlation of lipid indexes to MRI measures of disease severity in multiple sclerosis
(A) Heatmap inwhich each column represents anMRImeasure and each row represents the correlation to immunoglobulin G serumantibody reactivity to lipids accord-ing to a colorimetric scale (B) Scatter plots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the discovery set (C) Scatterplots depicting the correlation between each lipid index andMRImeasures (BPF GMF and T2LV) in the validation set BPF5whole brain parenchymal fraction GMF5
cerebral gray matter fraction (see methods section for details) T2LV 5 cerebral T2 hyperintense lesion volume WMF 5 global cerebral white matter fraction
8 Neurology Neuroimmunology amp Neuroinflammation
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
as well as oligoclonal bands or neurofilament-specificantibodies in CSF42ndash44 In the present study weanalyzed the association between serum antibodyprofiles detected with antigen microarrays and MRImeasures of disease including cerebral atrophy andT2 hyperintense lesions We found that specificantibody patterns are associated with different aspectsof MRI-defined disease pathology Our major findingwas that increased reactivity to lipids is associated withdifferent aspects of brain MRI measures of diseaseseverity Of note the specific set of lipids associatedwith atrophy differed from those associated withlesions Taken together these data suggest that anti-lipid antibodies in serum are related to MRI measuresof disease Our findings highlight the important role oflipid and lipid-specific immunity in the pathogenesis ofMS
Although a potential limitation of these studies isthe relatively small number of samples analyzed wehave validated our findings in an independent valida-tion cohort strengthening their significance In addi-tion further studies in large cohorts from patientsaffected by non-MS neurodegenerative diseases andhealthy controls may indicate whether the antibodyreactivities and lipid indexes identified in these stud-ies are exclusive to MS or are associated with addi-tional biological processes Indeed some of theseantibody reactivities contributing to the immune sig-natures described in this work have been found innewborns45
Different sets of antibody reactivities were associ-ated with GMF WMF BPF and T2LV The differ-ent antibody link between lesions and atrophy is inkeeping with the long-held view that brain atrophyin patients with MS is multifactorial and is onlyweakly related to lesions41 This has been underscoredin recent studies showing the complementary infor-mation obtained by combining lesion and atrophymeasures4647
Among the cerebral atrophy measures there was astriking overlap between those antibodies associatedwith GMF and BPF which separated them fromWMF results These findings are in keeping with pre-vious observations that whole brain atrophy is domi-nated by GM loss3741 In the early stages of MS thisGM atrophy selectively involves the deep GM nuclei34
Thus the similarities observed in the autoantibodieslinked to GMF and BPF might reflect the dominantcontribution and colinearity of GM atrophy to totalbrain atrophy The set of antibodies linked to GMFmay be the most relevant given that MRI studies haveshown that GM volume is more closely linked to phys-ical disability37 and cognitive impairment38 than areWM volume or lesion measures
Using antigen microarrays antibody reactivity tolipids has been detected in the CSF and serum of
patients with MS at different stages of the diseaseand such antibodies in the CSF have been linkedto disease progression and MRI involvement44
Although several mechanisms are thought to drivebrain inflammation and atrophy in MS46 the connec-tion between these mechanisms and the antibodiesdetected with our antigen microarrays is yet unknownOne possibility is that the serum autoantibodies iden-tified in our studies are not pathogenic and reflect theresult of immunization against self-antigens releasedfrom the CNS during the course of the disease Indeedneurofilament is released from damaged axons duringthe course of MS and both neurofilament lightchains48 and antibodies against it42 have been linkedto MRI measures of disease Moreover heat shockproteins are upregulated in different cell types duringinflammation and have been shown to have an impor-tant role as immunomodulators when released to theextracellular medium4950 Thus it is possible that heatshock proteinndashreactive antibodies reflect changes in theproduction and release of these immunomodulatorsduring the course of disease pathogenesis Similarlybioactive lipids and their products are released fromdamaged myelin and lipid-specific antibodies havebeen detected in patients with MS27293051 Lipids havean important role in the immune response both asbioactive molecules with immunomodulatory proper-ties and also as targets of the adaptive immuneresponse52 Moreover lipids have significant effectson the murine model of MS experimental autoim-mune encephalomyelitis2729305153 Indeed we recentlyfound that the glycolipid lactosylceramide activates abroad set of biological processes in astrocytes promot-ing neurodegeneration and inflammation53 Thus thelipid-reactive antibodies detected in this work mayreflect the release of myelin lipids in the context ofMS pathogenesis andor may directly contribute toimmune-mediated damage in CNS tissue Of notelipid-reactive antibodies are highly cross-reactive52 Inaddition the lipid-reactive antibodies detected in thiswork as associated with MRI measures of disease activ-ity were of the IgG class These are important points toconsider when evaluating a potential role of lipid-reactive antibodies inMS pathogenesis Further studiesare warranted to investigate whether bioactive lipidsoffer new therapeutic targets in MS
We have found that unique patterns of immunereactivity determined with antibody arrays are associ-ated with specific MRI measures of disease severityThese patterns agree with the interpretation that dif-ferent pathogenic mechanisms drive diverse diseaseprocesses reflected by these MRI measures These pat-terns also suggest a predominant role for lipids andlipid-specific immunity in MS pathology Furtherstudies are warranted to determine whether the earlyappearance of anti-lipid antibodies predicts the
Neurology Neuroimmunology amp Neuroinflammation 9
ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
subsequent development of clinical and MRI-defineddisease worsening
AUTHOR CONTRIBUTIONSRohit Bakshi draftingrevising the manuscript study concept or design
analysis or interpretation of data acquisition of data study supervision
obtaining funding Ada Yeste study concept or design acquisition of
data Bonny Patel analysis or interpretation of data statistical analysis
Shahamat Tauhid analysis or interpretation of data Subhash Tummala
analysis or interpretation of data Roya Rahbari analysis or interpretation
of data statistical analysis Renxin Chu analysis or interpretation of data
Keren Regev analysis or interpretation of data acquisition of data
Pia Kivisaumlkk draftingrevising the manuscript study concept or design
contribution of vital reagentstoolspatients acquisition of data study
supervision Howard L Weiner study concept or design obtaining fund-
ing Francisco J Quintana draftingrevising the manuscript study con-
cept or design contribution of vital reagentstoolspatients study
supervision obtaining funding
ACKNOWLEDGMENTThe authors thank Dr Mohit Neema Dr Antonella Ceccarelli and
Dr Ashish Arora for valuable assistance at the early stages of this project
STUDY FUNDINGThis work was supported in part by grants to FJQ and HLW from
EMD Serono RG4111A1 and JF2161-A-5 from the National Multiple
Sclerosis Society PA0069 from the International Progressive MS Alli-
ance and by grants from the NIH (5R01NS055083-04) and NMSS
(RG3798A2) to RB
DISCLOSUREFJ Quintana serves on the editorial board for Systems Biomedicine
Inmunologia American Journal of Clinical and Experimental Immunology
is an associate editor for Immunology (UK) is an advisory board member
for Seminars in Immunopathology received research support from Harvard
Medical School BADERC NMSS A Yeste and B Patel report no
disclosures S Tauhid is managing editor for Journal of Neuroimaging
S Tummala R Rahbari R Chu and K Regev report no disclosures
P Kivisaumlkk received research support from EMD Serono R Bakshi is
editor-in-chief for Journal of Neuroimaging received consulting fees from
AbbVie Alkermes Biogen Novartis Questcor received research support
from Biogen EMD-Serono Novartis Sanofi-Genzyme Teva his spouse
holds stock in Biogen Inc H Weiner served on the advisory board
for The Guthy-Jackson Charitable Foundation Teva Pharmaceuticals
Industries Ltd Biogen Idec Novartis Sanofi-Aventis has consulted for
Therapix Bioven Novartis Serono Teva Sanofi received research support
from National Multiple Sclerosis Society Go to Neurologyorgnn for full
disclosure forms
Received July 27 2015 Accepted in final form December 8 2015
REFERENCES1 Weiner HL The challenge of multiple sclerosis how do
we cure a chronic heterogeneous disease Ann Neurol
200965239ndash248
2 Bakshi R Thompson AJ Rocca MA et al MRI in mul-
tiple sclerosis current status and future prospects Lancet
Neurol 20087615ndash625
3 Ceccarelli A Bakshi R Neema M MRI in multiple scle-
rosis a review of the current literature Curr Opin Neurol
201225402ndash409
4 Filippi M Rocca MA Barkhof F et al Association
between pathological and MRI findings in multiple scle-
rosis Lancet Neurol 201211349ndash360
5 Geurts JJ Calabrese M Fisher E Rudick RA Measure-
ment and clinical effect of grey matter pathology in mul-
tiple sclerosis Lancet Neurol 2012111082ndash1092
6 Klaver R De Vries HE Schenk GJ Geurts JJ Grey mat-
ter damage in multiple sclerosis a pathology perspective
Prion 2013766ndash75
7 Khoury S Bakshi R Cerebral pseudoatrophy or real atro-
phy after therapy in multiple sclerosis Ann Neurol 2010
68778ndash779
8 Hauser SL Chan JR Oksenberg JR Multiple sclerosis
prospects and promise Ann Neurol 201374317ndash327
9 McFarland HF Martin R Multiple sclerosis a complicated
picture of autoimmunity Nat Immunol 20078913ndash919
10 Nylander A Hafler DA Multiple sclerosis J Clin Invest
20121221180ndash1188
11 Sospedra M Martin R Immunology of multiple sclerosis
Ann Rev Immunol 200523683ndash747
12 Steinman L Immunology of relapse and remission in mul-
tiple sclerosis Ann Rev Immunol 201432257ndash281
13 Khoury SJ Guttmann CR Orav EJ Kikinis R Jolesz FA
Weiner HL Changes in activated T cells in the blood
correlate with disease activity in multiple sclerosis Arch
Neurol 2000571183ndash1189
14 Khoury SJ Orav EJ Guttmann CR Kikinis R Jolesz FA
Weiner HL Changes in serum levels of ICAM and TNF-
R correlate with disease activity in multiple sclerosis Neu-
rology 199953758ndash764
15 Laplaud DA Berthelot L Miqueu P et al Serial blood T
cell repertoire alterations in multiple sclerosis patients cor-
relation with clinical and MRI parameters J Neuroimmunol
2006177151ndash160
16 Makhlouf K Weiner HL Khoury SJ Increased percentage
of IL-121 monocytes in the blood correlates with the
presence of active MRI lesions in MS J Neuroimmunol
2001119145ndash149
17 Prat A Biernacki K Saroli T et al Kinin B1 receptor expres-
sion on multiple sclerosis mononuclear cells correlation with
magnetic resonance imaging T2-weighted lesion volume and
clinical disability Arch Neurol 200562795ndash800
18 Rinaldi L Gallo P Calabrese M et al Longitudinal anal-
ysis of immune cell phenotypes in early stage multiple
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
26 Lalive PH Menge T Barman I Cree BA Genain CP
Identification of new serum autoantibodies in neuromye-
litis optica using protein microarrays Neurology 200667
176ndash177
27 Kanter JL Narayana S Ho PP et al Lipid microarrays
identify key mediators of autoimmune brain inflamma-
tion Nat Med 200612138ndash143
28 Quintana FJ Farez MF Izquierdo G Lucas M Cohen IR
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
1
Table e-1 Antigens used
Group Antigen Source
27 kDa Heat Shock Protein Stressgen
HSP 32 kDa Heat Shock Protein Stressgen
40 kDa Heat Shock Protein Stressgen
47 kDa Heat Shock Protein Stressgen
60 kDa Heat Shock Protein Stressgen
60 kDa Heat Shock Protein peptide aa 106ndash125 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 121ndash140 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 136ndash155 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 151ndash170 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 16ndash35 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 166ndash185 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 181ndash199 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 195ndash214 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 210ndash229 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 225ndash244 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 240ndash259 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 255ndash275 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 271ndash290 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 286ndash305 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 301ndash320 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 31ndash50 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 316ndash335 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 331ndash350 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 346ndash365 Biopolymers Facility Harvard Medical School
2
60 kDa Heat Shock Protein peptide aa 361ndash380 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 376ndash395 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 391ndash410 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 406ndash425 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 421ndash440 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 436ndash455 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 451ndash470 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 466ndash485 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 46ndash65 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 481ndash500 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 496ndash515 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 511ndash530 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 526ndash545 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 541ndash560 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 556ndash573 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
65 kDa Heat Shock Protein M tuberculosis Stressgen
70 kDa Heat Shock Protein Stressgen
70 kDa Heat Shock Protein peptide aa 106ndash125 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 121ndash140 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 136ndash155 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 151ndash170 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 16ndash35 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 166ndash185 Biopolymers Facility Harvard Medical School
3
70 kDa Heat Shock Protein peptide aa 181ndash199 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 195ndash214 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 210ndash229 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 225ndash244 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 240ndash259 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 255ndash275 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 271ndash290 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 286ndash305 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 301ndash320 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 31ndash50 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 316ndash335 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 331ndash350 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 346ndash365 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 361ndash380 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 376ndash395 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 391ndash410 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 406ndash425 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 421ndash440 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 436ndash455 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 451ndash470 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 466ndash485 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 46ndash65 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 481ndash500 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 496ndash515 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 511ndash530 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 526ndash545 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 541ndash560 Biopolymers Facility Harvard Medical School
4
70 kDa Heat Shock Protein peptide aa 556ndash575 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 571ndash590 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 586ndash605 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 601ndash620 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 616ndash635 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 631ndash640 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
71 kDa Heat Shock Protein M tuberculosis Biopolymers Facility Harvard Medical School
90 kDa Heat Shock Protein Stressgen
GroEL Stressgen
23-cyclic nucleotide 3-phosphodiesterase
peptide aa106-125 Biopolymers Facility Harvard Medical School
CNS
23-cyclic nucleotide 3-phosphodiesterase
peptide aa1-20 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa121-140 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa136-155 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa151-170 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa16-35 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa166-185 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase Biopolymers Facility Harvard Medical School
5
peptide aa181-200
23-cyclic nucleotide 3-phosphodiesterase
peptide aa196-215 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa211-230 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa226-245 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa241-260 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa256-275 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa271-290 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa286-305 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa301-320 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa31-50 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa316-335 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa331-350 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa346-365 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa361-380 Biopolymers Facility Harvard Medical School
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
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2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
2
60 kDa Heat Shock Protein peptide aa 361ndash380 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 376ndash395 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 391ndash410 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 406ndash425 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 421ndash440 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 436ndash455 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 451ndash470 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 466ndash485 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 46ndash65 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 481ndash500 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 496ndash515 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 511ndash530 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 526ndash545 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 541ndash560 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 556ndash573 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
60 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
65 kDa Heat Shock Protein M tuberculosis Stressgen
70 kDa Heat Shock Protein Stressgen
70 kDa Heat Shock Protein peptide aa 106ndash125 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 121ndash140 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 136ndash155 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 151ndash170 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 16ndash35 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 166ndash185 Biopolymers Facility Harvard Medical School
3
70 kDa Heat Shock Protein peptide aa 181ndash199 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 195ndash214 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 210ndash229 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 225ndash244 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 240ndash259 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 255ndash275 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 271ndash290 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 286ndash305 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 301ndash320 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 31ndash50 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 316ndash335 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 331ndash350 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 346ndash365 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 361ndash380 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 376ndash395 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 391ndash410 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 406ndash425 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 421ndash440 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 436ndash455 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 451ndash470 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 466ndash485 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 46ndash65 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 481ndash500 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 496ndash515 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 511ndash530 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 526ndash545 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 541ndash560 Biopolymers Facility Harvard Medical School
4
70 kDa Heat Shock Protein peptide aa 556ndash575 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 571ndash590 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 586ndash605 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 601ndash620 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 616ndash635 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 631ndash640 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
71 kDa Heat Shock Protein M tuberculosis Biopolymers Facility Harvard Medical School
90 kDa Heat Shock Protein Stressgen
GroEL Stressgen
23-cyclic nucleotide 3-phosphodiesterase
peptide aa106-125 Biopolymers Facility Harvard Medical School
CNS
23-cyclic nucleotide 3-phosphodiesterase
peptide aa1-20 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa121-140 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa136-155 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa151-170 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa16-35 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa166-185 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase Biopolymers Facility Harvard Medical School
5
peptide aa181-200
23-cyclic nucleotide 3-phosphodiesterase
peptide aa196-215 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa211-230 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa226-245 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa241-260 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa256-275 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa271-290 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa286-305 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa301-320 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa31-50 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa316-335 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa331-350 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa346-365 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa361-380 Biopolymers Facility Harvard Medical School
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
3
70 kDa Heat Shock Protein peptide aa 181ndash199 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 195ndash214 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 210ndash229 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 225ndash244 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 240ndash259 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 255ndash275 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 271ndash290 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 286ndash305 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 301ndash320 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 31ndash50 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 316ndash335 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 331ndash350 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 346ndash365 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 361ndash380 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 376ndash395 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 391ndash410 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 406ndash425 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 421ndash440 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 436ndash455 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 451ndash470 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 466ndash485 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 46ndash65 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 481ndash500 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 496ndash515 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 511ndash530 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 526ndash545 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 541ndash560 Biopolymers Facility Harvard Medical School
4
70 kDa Heat Shock Protein peptide aa 556ndash575 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 571ndash590 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 586ndash605 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 601ndash620 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 616ndash635 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 631ndash640 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
71 kDa Heat Shock Protein M tuberculosis Biopolymers Facility Harvard Medical School
90 kDa Heat Shock Protein Stressgen
GroEL Stressgen
23-cyclic nucleotide 3-phosphodiesterase
peptide aa106-125 Biopolymers Facility Harvard Medical School
CNS
23-cyclic nucleotide 3-phosphodiesterase
peptide aa1-20 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa121-140 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa136-155 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa151-170 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa16-35 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa166-185 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase Biopolymers Facility Harvard Medical School
5
peptide aa181-200
23-cyclic nucleotide 3-phosphodiesterase
peptide aa196-215 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa211-230 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa226-245 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa241-260 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa256-275 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa271-290 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa286-305 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa301-320 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa31-50 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa316-335 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa331-350 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa346-365 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa361-380 Biopolymers Facility Harvard Medical School
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
4
70 kDa Heat Shock Protein peptide aa 556ndash575 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 571ndash590 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 586ndash605 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 601ndash620 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 616ndash635 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 61ndash80 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 631ndash640 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 76ndash95 Biopolymers Facility Harvard Medical School
70 kDa Heat Shock Protein peptide aa 91ndash110 Biopolymers Facility Harvard Medical School
71 kDa Heat Shock Protein M tuberculosis Biopolymers Facility Harvard Medical School
90 kDa Heat Shock Protein Stressgen
GroEL Stressgen
23-cyclic nucleotide 3-phosphodiesterase
peptide aa106-125 Biopolymers Facility Harvard Medical School
CNS
23-cyclic nucleotide 3-phosphodiesterase
peptide aa1-20 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa121-140 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa136-155 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa151-170 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa16-35 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa166-185 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase Biopolymers Facility Harvard Medical School
5
peptide aa181-200
23-cyclic nucleotide 3-phosphodiesterase
peptide aa196-215 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa211-230 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa226-245 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa241-260 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa256-275 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa271-290 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa286-305 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa301-320 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa31-50 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa316-335 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa331-350 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa346-365 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa361-380 Biopolymers Facility Harvard Medical School
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
5
peptide aa181-200
23-cyclic nucleotide 3-phosphodiesterase
peptide aa196-215 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa211-230 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa226-245 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa241-260 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa256-275 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa271-290 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa286-305 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa301-320 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa31-50 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa316-335 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa331-350 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa346-365 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa361-380 Biopolymers Facility Harvard Medical School
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
6
23-cyclic nucleotide 3-phosphodiesterase
peptide aa376-395 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa391-410 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa406-421 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa46-65 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa61-80 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa76-95 Biopolymers Facility Harvard Medical School
23-cyclic nucleotide 3-phosphodiesterase
peptide aa91-110 Biopolymers Facility Harvard Medical School
Acetyl Cholinesterase Sigma Aldrich
ADAM-10 Sigma Aldrich
alpha-Cristallin Stressgen
beta-Cristallin Sigma Aldrich
bovine Myelin Basic Protein Sigma Aldrich
Brain Extract I Sigma Aldrich
Brain Extract II Sigma Aldrich
Brain Extract III Sigma Aldrich
Glial Filament Acidic Protein Research Diagnostic
guinea pig Myelin Basic Protein Sigma Aldrich
human Myelin Basic Protein Sigma Aldrich
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 106-125 Biopolymers Facility Harvard Medical School
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
7
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 121-140 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 136-155 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 151-170 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 166-185 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 181-200 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin-Associated Oligodendrocytic Basic Protein
peptide aa 91-110 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
106-125 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa 1- Biopolymers Facility Harvard Medical School
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
8
20
Myelinoligodendrocyte glycoprotein peptide aa
121-140 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
136-155 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
151-170 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
16-35 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
166-185 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
181-200 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
196-215 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
211-230 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
226-247 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
31-50 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
35-55 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
46-65 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
61-80 Biopolymers Facility Harvard Medical School
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
9
Myelinoligodendrocyte glycoprotein peptide aa
76-95 Biopolymers Facility Harvard Medical School
Myelinoligodendrocyte glycoprotein peptide aa
91-110 Biopolymers Facility Harvard Medical School
murine Myelin Basic Protein Sigma Aldrich
Myelin Associated Glycoprotein Sigma Aldrich
Myelin Basic Protein peptide aa 104-123 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 11-30 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 113-132 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 121-138 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 124-142 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 138-147 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 141-161 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 143-168 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 155-178 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 26-35 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 41-60 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 51-70 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 71-92 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 84-94 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 89-101 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 173-186 Biopolymers Facility Harvard Medical School
Myelin Basic Protein peptide aa 93-112 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 106-125 Biopolymers Facility Harvard Medical School
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
10
Myelin Protein 2 peptide aa 1-20 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 121-132 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 16-35 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 31-50 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 46-65 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 61-80 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 76-95 Biopolymers Facility Harvard Medical School
Myelin Protein 2 peptide aa 91-110 Biopolymers Facility Harvard Medical School
Neurofilament 160kd Chemicon
Neurofilament 200kd Chemicon
Neurofilament 68kd Chemicon
Neuronal Enolase Calbiochem
Nicastrin GeneTex
NMDA receptor Novus Biologicals
NOGO Sigma Aldrich
Olygodendrocyte-Specific Protein peptide aa 106ndash
125 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 1ndash20 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 121ndash
140 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 136ndash
155 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 151ndash
170 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 16ndash
35 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 166ndash Biopolymers Facility Harvard Medical School
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
11
185
Olygodendrocyte-Specific Protein peptide aa 181ndash
199 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 195ndash
217 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 31ndash
50 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 46ndash
65 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 61ndash
80 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 76ndash
95 Biopolymers Facility Harvard Medical School
Olygodendrocyte-Specific Protein peptide aa 91ndash
110 Biopolymers Facility Harvard Medical School
Proteolipid Protein Abnova
Proteolipid Protein peptide aa 100-119 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 10-29 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 110-129 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 1-19 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 125-141 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-150 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 137-154 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 150-163 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 151-173 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 158-166 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 161-180 Biopolymers Facility Harvard Medical School
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
12
Proteolipid Protein peptide aa 178-191 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 180-199 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 190-209 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 20-39 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 205-220 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 215-232 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-239 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 220-249 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 248-259 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 250-269 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 265-277 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 35-50 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 40-59 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 50-69 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 65-84 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 80-99 Biopolymers Facility Harvard Medical School
Proteolipid Protein peptide aa 91-110 Biopolymers Facility Harvard Medical School
Retinol Binding Protein Sigma Aldrich
S100beta protein Assay Designs
Super Oxide Dismutase Sigma Aldrich
Synuclein beta Sigma Aldrich
Synuclein gamma Sigma Aldrich
Amydgala ProSci Inc
Tissue Amydgala AD ProSci Inc
Brain lysate ProSci Inc
Brain Tissue Membrane ProSci Inc
Cerebellar pedunculus ProSci Inc
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
13
Cerebral meninges ProSci Inc
Corpus Callosum ProSci Inc
Corpus Callosum AD ProSci Inc
Diencephalon ProSci Inc
Fetal brain ProSci Inc
Frontal lobe ProSci Inc
Frontal lobe AD ProSci Inc
Hippocampus ProSci Inc
Hippocampus AD ProSci Inc
Insula ProSci Inc
Occipital lobe ProSci Inc
Occipital lobe AD ProSci Inc
Olfactory region ProSci Inc
Optic Nerve ProSci Inc
Parietal lobe ProSci Inc
Parietal lobe AD ProSci Inc
Pons ProSci Inc
Pons AD ProSci Inc
Postcentral gyrus ProSci Inc
Postcentral gyrus AD ProSci Inc
Precentral gyrus ProSci Inc
Precentral gyrus AD ProSci Inc
Spinal cord ProSci Inc
Temporal lobe ProSci Inc
Temporal lobe AD ProSci Inc
Thalamus ProSci Inc
Thalamus AD ProSci Inc
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
14
Amyloid beta Sigma Aldrich
AD
related Amyloid beta 10-20 Sigma Aldrich
Amyloid beta 1-12 Sigma Aldrich
Amyloid beta 12-28 Sigma Aldrich
Amyloid beta 1-23 Sigma Aldrich
Amyloid beta 1-38 Sigma Aldrich
Amyloid beta 17-40 Sigma Aldrich
Amyloid beta 25-35 Sigma Aldrich
Amyloid beta 34-42 Sigma Aldrich
Amyloid bri protein precursor 227 Sigma Aldrich
Amyloid DAN Protein Fragment 1-34 Sigma Aldrich
Amyloid Precursor Protein Sigma Aldrich
Amyloid protein no AB component Sigma Aldrich
Secreted amyloid precursor protein (SAP) beta Sigma Aldrich
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
17
Squalene Sigma Aldrich
Sulfatides Sigma Aldrich
Tetracosanoic acid (24) Sigma Aldrich
Tetrasialoganglioside-GQ1B Calbiochem
TNPAL Galactocerebroside Sigma Aldrich
Total brain gangliosides Avanti Polar Lipids
Total cerebroside Avanti Polar Lipids
Trisialoganglioside GT1a HyTest
Trisialoganglioside-GT1B Sigma Aldrich
DOI 101212NXI000000000000020020163 Neurol Neuroimmunol Neuroinflamm
Rohit Bakshi Ada Yeste Bonny Patel et al Serum lipid antibodies are associated with cerebral tissue damage in multiple sclerosis
This information is current as of January 27 2016
ServicesUpdated Information amp
httpnnneurologyorgcontent32e200fullhtmlincluding high resolution figures can be found at
Supplementary Material httpnnneurologyorgcontentsuppl2016012732e200DC1html
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
BakshiLipidsMRIN216
Table_e-1
DOI 101212NXI000000000000020020163 Neurol Neuroimmunol Neuroinflamm
Rohit Bakshi Ada Yeste Bonny Patel et al Serum lipid antibodies are associated with cerebral tissue damage in multiple sclerosis
This information is current as of January 27 2016
ServicesUpdated Information amp
httpnnneurologyorgcontent32e200fullhtmlincluding high resolution figures can be found at
Supplementary Material httpnnneurologyorgcontentsuppl2016012732e200DC1html
httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm