6/18/2015 1 Role of the Immune System(s) in Progressive MS Amit Bar-Or,, Professor, Neuroimmunology Director, Experimental Therapeutics Program Scientific Director, Clinical Research Unit Montreal Neurological Institute, McGill University CMSC Annual Meeting Indianapolis, May 2015 I have participated as a speaker at meetings sponsored by, received consulting fees, and/or grant support from: Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme EMD/Merck Serono, GSK, Mitsubishi Pharma, Novartis, Receptos, Roche,, Teva Neuroscience Investigational and off label agents may be discussed. Disclosures
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6/18/2015
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Role of the Immune System(s) in Progressive MS
Amit Bar-Or,, Professor, Neuroimmunology
Director, Experimental Therapeutics ProgramScientific Director, Clinical Research Unit
Montreal Neurological Institute, McGill University
CMSC Annual MeetingIndianapolis, May 2015
I have participated as a speaker at meetings sponsored by, received consulting fees, and/or grant support from:
Investigational and off label agents may be discussed.
Disclosures
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Concepts of inflammation and degeneration in MS: [Inflammation throughout MS spectrum (lesion axon loss microglial activation); divide into periph infilt vs CNS compartm]
How soon might it start – PD MS evidence (imaging, recent pathology - Bruck)?
Mechanisms: Adaptive (T and B specificity; ? Target/ pediatric Axoglial?) vs Innate (bystander; chronic microglial activation – more later)
Direct inflamma damage vs. indirect (impacting degeneration –eg OPC failed repair, astrocyte support, of OPC, neurons eg NK; exacerbate metabolic stress/demand/mitochondria, channelopathies etc
Single vs multi-hit (eg Jack’s Oligo model, then Moore et al direct inflamm/OPC or via astrocytes)
CNS compartmentalized – evidence late (Renyolds); early (Lucchinetti): microglia – Nat Neurosci
January 2002 February 2003 November 2004
Multi-focal (and diffuse) injury evolving over time
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Outline
Concepts of inflammation and degeneration in MS
Multi-hit model
Direct and Indirect immune effects
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Mechanisms above also likely contribute to limited repair
Loss of compensatory mechanisms + Ageing
ALS: Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective. Malaspina A, et al. Int Immunol. 2015.
AzD: Neuronal NLRP1 inflammasome activation regulates inflammatory interleukin‐1‐beta production and axonal degeneration. Kaushal V, et al. Cell Death Differ. 2015.
Chronic Epilepsy: NLRP1 inflammasome is activated in patients with TLE and contributes to neuronal pyroptosis. Tan CC, et al. J Neuroinflammation. 2015
MPS: Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model. Martins C, et al. Brain. 2015.
Ceroid lipofuscinosis: An anti‐neuroinflammatory that targets dysregulated glia enhances efficacy of CNS‐directed gene therapy in infantile neuronal ceroid lipofuscinosis. Macauley SL, et al. J Neurosci. 2014.
Innate inflammation in multiple neurodegenerative diseases
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A BrainNet Europe gene expression microarray study. Durrenberger PF, et al. J Neural Transm. 2014.
Comparative genome-wide expression data (Illumina H-Ref 8)
AzD, ALS, HD, MS, PD, MS and Schizophrenia (n = 113 well-characterized post-mortem brain tissues).
Results: no dysregulated gene (passing QC) found across all 61 dysregulated genes shared when comparing 4+5 diseases)
Hints for common neuronal homeostatic, survival and synaptic plasticity pathways.
All diseases exhibited changes in several inflammation-related genes …role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
Are there common mechanisms across diseases?
Outline
Concepts of inflammation and degeneration in MS
Cellular and molecular mechanisms by which inflammation may contribute to CNS degeneration
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Emerging roles of:
(i) Glial influences on neuronal physiology
(ii) Immune:Glial interactions impacting neurons
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Outline
Concepts of inflammation and degeneration in MS
Cellular and molecular mechanisms by which inflammation may contribute to CNS degeneration
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Emerging roles of:
(i) Glial influences on neuronal physiology
(ii) Immune:Glial interactions impacting neurons
Astrocyte and Microglia Biology: Novel functions and distinct subsets impacting OPC and Neurons
Molecular and functional microglia signaturesButovsky O, et al. Nat Neurosci. 2014
Glia-glia interactions: astrocyte and microglia effects on OPC during development and demyelinating disease.Clemente D et al. Front Cell Neurosci. 2013
Astrocytes-neuron signaling in brain.Tang F, et al. Nat Commun. 2014
Glial cells in progressive CNS injury and repair
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Several important neuronal–glial interactions recognized
Synapse loss is striking in neurodegenerative disease and
Glia have intimate roles in synapse physiology:
Astrocytes, OL, and microglia: All crucial and multifaceted roles in maintenance of synaptic function and excitability.
Neuroinflammation contribution to synapse loss may be primarily mediated by altered glial functions.
Question: how does Inflammation (aging, neuronal stress) impact on glia (eg activation) neurons/synapses
Glia: guardians, gluttons, or guides for maintenanceof neuronal connectivity? Jebelli, et al; Ann NY Acad Sci. 2015.
Microglial p53 activation is detrimental to neuronal synapses during activation-induced inflammation: Implications for neurodegeneration. Jebelli J, et al. Neurosci Lett. 2014.
Neurodegeneration by activation of the microglial complement-phagosome pathway. Bodea LG, et al. J Neurosci. 2014.
System xC- is a mediator of microglial function; its deletion slows symptoms in ALS mice. Mesci P, et al Brain. 2015.
SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. Cho SH, et al. J Neurosci. 2015.
A DAP12-Dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons. Kobayashi M, et al. Glia. 2015
Adaptive Immune: T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. González H and Pacheco R. J Neuroinflammation. 2014.
Possible Mechanisms of Inflammation Degeneration
Innate immune: Inflammasome, TLR, Complement, Vesicles:The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration.Rosenberger K, et al. J Neuroinflammation. 2014.
Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Orsini F. et al. Front Cell Neurosci. 2014.
Emerging roles of extracellular vesicles in the nervous system. Rajendran L, et al. J Neurosci. 2014.
The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?Doty KR, et al. Brain Res. 2014.
Neuroinflammation: Take the Bad with the Good?
Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy. Villacampa N, et al. Glia. 2015.
Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1-42-Induced Alzheimer's Disease Model Rats. Chen Jh et al. PLoS One. 2015.
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Microglia signature (gene expression and quantitative mass spectrometry) suggests ‘Maintainers of CNS quiescence’
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. Jay TR, et al. J Exp Med. 2015.
However:
TREM2 Lipid Sensing Sustains the Microglial desired Response in an Alzheimer's Disease Model. Wang Y, et al Cell. 2015
Adapted from Hohlfeld R et al. J Neuroimmunol. 2000;107:161-166.
The Two Sides of Inflammation
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Mechanisms that may underlie Progressive (‘non relapsing’) CNS injury
Mechanisms above also likely contribute to limited repair
Loss of compensatory mechanisms + Ageing
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Outline
Concepts of inflammation and degeneration in MS
Multi-hit model
Direct and Indirect immune effects
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Emerging roles of inflammation impacting:
(i) Glial influences on neuronal physiology
(ii) Immune:Glial interactions impacting neurons
Adaptive and Innate immune responses
Outline
Concepts of inflammation and degeneration in MS
Multi-hit model
Direct and Indirect immune effects
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Emerging roles of inflammation impacting:
(i) Glial influences on neuronal physiology
(ii) Immune:Glial interactions impacting neurons
Adaptive and Innate immune responses
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‘Multi-hit’ Model of Oligodendrocyte Injury
P53
• Inflammation• Ischemia• Infection • Trauma
p53 upregulation Sublethal injury
Death receptor upregulation
Fas
DR4/5
Death receptor triggering and apoptotic signalling Lethal injury
IFNgTNFa
T cellMicroglia
ROS
From Antel J. Clin Neurol Neurosurg. 2005
P53
• Inflammation• Ischemia• Infection • Trauma
p53 upregulation Sublethal injury
Death receptor upregulation
Fas
DR4/5
Death receptor triggering and apoptotic signalling Lethal injury
IFNgTNFa
T cellMicroglia
ROS
From Antel J. Clin Neurol Neurosurg. 2005
‘Multi-hit’ Model of Oligodendrocyte Injury
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P53
• Inflammation• Ischemia• Infection • Trauma
p53 upregulation Sublethal injury
Death receptor upregulation
Fas
DR4/5
Death receptor triggering and apoptotic signalling Lethal injury
IFNgTNFa
T cellMicroglia
ROS
From Antel J. Clin Neurol Neurosurg. 2005
‘Multi-hit’ Model of Oligodendrocyte Injury
From: Darlington P, et al J Neuropathol Exp Neurol. 2008
Human neurons live on ‘bed’ of astrocytes
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Immune cells can injure astrocytes with secondary injury to neurons
From: Darlington P, et al J Neuropathol Exp Neurol. 2008
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Reproduced with permission from Kutzelnigg A et al. Brain. 2005;128:2705-2712.
Subpial cortical demyelination in progressive MS
Kutzelnigg, A. et al. Brain 128:2705-2712; 2005
Meningeal inflammation in MS can be ‘B cell rich’
Howell OW, et al Brain. 2011
Uccelli et al, Trends Immunol 2005;
Corcione et al Autoimmunity Rev 2005
CD20
CD35
B C
CD20
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Cortical lesions: correlation with disease course, including disability and cognitive deficits (Howell OW, et al Brain. 2011 Sep;134(Pt 9):2755-71)
Microglial activation – identical gradient graded inflammatory process from pial surface in (Magliozzi R, et al Ann Neurol. 2010 Oct;68(4):477-93)
Subpial Cortical Lesions Exhibit Gradient of neuronal loss
Cortical layers
Magliozzi et al, 2010 Ann Neurol
Human Glial Cells/Neuroglia
OligodendrocyteAstrocyteMicroglia OPC
Trypsin
DNase
Percoll toremove myelin
Wash
5% MEM/DMEMMicroglia adherentOligos, others float
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‘State’ of myeloid cell: Balance betweenActivation and Quiescence/Inhibitory molecules
Microglia or
Macrophage
CD80
CCR7
HLA-DR
CX3CR1
SIRP1α
TREM-2
CD200R
Csfr
Adapted from Kierdorf et al., Frontiers in Cell Neuroscience 2013Hanane Touil
+ Unp B sup Activation/Quiescence markers (FACS +
qPCR)Purified Human
Microglia orMacrophage
Methods: effects of Breg and Beff products on microglia and macrophage Activation/Quiescence molecules
Hanane Touil
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p p p0
5
10
15
20
25
mR
NA
Fo
ld C
ha
nge
HLA-DR
CCR7
0
2
4
6
8
mR
NA
Fo
ld c
ha
ng
e
0
10
20
30
40
mR
NA
F
old
Ch
an
ge
CD80
Human Microglia
Effects of Breg & Beff products on activation molecule expression by human macrophage and microglia
0
1
2
3
mR
NA
Fo
ld C
hang
e
p p p0.0
0.5
1.0
1.5
2.0
2.5
mR
NA
Fold
Change
HLA-DR
CCR7Human Macrophages
p p p0.0
0.5
1.0
1.5
2.0
mR
NA
Fo
ld C
ha
ng
e
CD80
Human Macrophages
0
2
4
6
8
10
mR
NA
Fo
ld C
ha
ng
e
TREM-2
0
10
20
30
mR
NA
Fo
ld C
han
ge
mCsfrp g p
0
10
20
30
mR
NA
Fo
ld C
ha
ng
e
SIRP1α
Human Microglia
0.0
0.5
1.0
1.5
2.0
2.5
mR
NA
Fo
ld C
ha
ng
e
TREM-2p
0
1
2
3
mR
NA
Fo
ld C
ha
ng
e
SIRP1α
0
1
2
3
4
mR
NA
Fo
ld C
ha
ng
e
mCsfr
Effects of Breg & Beff products on quiescence/inhibitory molecule expression by human macrophage and microglia
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Outline
Concepts of inflammation and degeneration in MS
Multi-hit model
Direct and Indirect immune effects
How soon might it start?
Inflammation invoked in Neurodegenerative Diseases
Emerging roles of inflammation impacting:
(i) Glial influences on neuronal physiology
(ii) Immune:Glial interactions impacting neurons
Adaptive and Innate immune responses
January 2002 February 2003 November 2004
Multi-focal (and diffuse) injury evolving over time
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Neurology. 2012 Jan 17;78(3):194-201
Summary: Inflammation in Progressive MSInflammation appears to be involved throughout MS spectrum; contributes in different ways in different CNS sub-compartments
Perivascular, diffuse, meningeal
Roles for both adaptive and innate; likely Innate > Adaptive
Important interface between inflammatory and degenerative mechanisms
Glial cells (microglia, astrocytes) as mediators of inflammation
Both direct and indirect injury mechanisms; ‘multiple hit’ model
‘Progressive disease biology’ may start earlier than we would like to think!
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Thanks to:
CIHR, MSSC, ITN/NIH, Wadsworth, CIHR/IHRT, MSSC Scientific Research Foundation
Valuable insights from comparing across diseases(Similarities and important differences)
Emerging roles of glial cells: neuronal integrity/function
Underscores importance of understanding both Neuronal:glial and Glial:Glial interactions
Neuroinflammation Glial state Neurodegeneration
Mechanisms may be starting at the very beginning…
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InflammatoryCNS Injury
A. DegenerativeCNS Injury
Bar-Or A. Advances in Neurology.;23:149-175, 2006
B. DegenerativeCNS Injury
DysregulatedImmune Response
InflammatoryCNS Injury
DysregulatedImmune
Response
Two Views on Neuro-Immunology of MS
Two Views on Neuro-Immunology of MS
InflammatoryCNS Injury
A. DegenerativeCNS Injury
B. DegenerativeCNS Injury
DysregulatedImmune Response
InflammatoryCNS Injury
Bar-Or A. Advances in Neurology.;23:149-175, 2006
DysregulatedImmune
Response
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Approach: Blinded ‘unbiased’ proteomics of CSF obtained at time of initial episode of pediatric CNS inflammatory demyelination*
Subsequent ascertainment as MS (vs monophasic)
Hypothesis: Compact myelin antigens (MBP, PLP), traditionally considered disease-initiating, will be over-represented in CSF of children with MS than controls
Pediatric MS CSF may better reflect Early MS targets
* Canadian Pediatric Demyelinating Disease Study
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Less known features:
? Impact of ‘peripheral/relapsing inflammation’ on ‘CNS-compartmentalized inflammation’
Reprinted from Bar-Or A. Semin Neurol. 2008;28(1):29–45;Copyright 2008,Thieme Publishing Group.
Identification of a microglia signature by gene expression and quantitative mass spectrometry (AffyExon1 & MG400 chip)
Nat. Neurosci. 2014 Jan;17(1):131-43
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PRE-HSCT POST-HSCT
RE
LAP
SE
S D
UR
ING
2
YE
AR
PE
RIO
D
0
1
2
3
4
n=14
Immune ablation and autologous stem cell reconstitution*(BMT) essentially halts measures of new focal disease activity
* With M. Freedman, H. Atkins, D. Arnold, J. Chen, and the Canadian Collaborative BMT in MS Study Group
NU
MB
ER
OF
GD
+
LE
SIO
NS
PE
R S
CA
N
MONTHS POST-HSCT
BL
1
1 2 4 6 9 12 15 18 24
BL
2
0
5
10
15
20
25
MONTHS POST-HSCT
NU
MB
ER
OF
NE
W T
2 LE
SIO
NS
BL1-BL2 1 2 4 6 9 12 15 18 24
0
5
10
20
Darlington et al, Ann Neurol, 2013
Hawker K, et al. Ann Neurol. 2009;66:460–71.
Effects of B cell Depletion in PPMS
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Preplanned subgroup analyses
Effects of B cell Depletion in PPMS
Hawker K, et al. Ann Neurol. 2009;66:460–71.
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Presence of IgM OCB (M+) was associated strongly with presence of Gd+ lesions in PPMS
Villar et al Ann Neurol 2014
Gd+ lesions continued in M+ treated with placebo ..
No new Gd+ lesions in M+ treated with rituximab.
B cell depletion decreased IgM OCB but not IgG OCB:
Villar et al Ann Neurol 2014
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Peripheral Inflammation in PPMS (vs RRMS, SPMS)
Several studies – no clear convergence/conclusion
“We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus.”
Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Quintana FJ; PNAS U S A. 2008
Not convinced that relevant differences have been established between peripheral immune responses in PPMS and SPMS
Peripheral Inflammation in PPMS (vs RRMS, SPMS)
Several studies – no clear convergence/conclusion
“We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus.”
Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Quintana FJ; PNAS U S A. 2008