Review Article The Pathology of T Cells in Systemic Lupus ...downloads.hindawi.com/journals/jir/2014/419029.pdf · The Pathology of T Cells in Systemic Lupus Erythematosus AnselmMak

Review ArticleThe Pathology of T Cells in Systemic Lupus Erythematosus

Anselm Mak12 and Nien Yee Kow2

1 Division of Rheumatology Department of Medicine University Medicine Cluster 1E Kent Ridge Road Level 10NUHS Tower Block Singapore 119228

2Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore 119228

Correspondence should be addressed to Anselm Mak anselm maknuhsedusg

Received 19 February 2014 Revised 12 March 2014 Accepted 12 March 2014 Published 23 April 2014

Academic Editor Xiuli Wu

Copyright copy 2014 A Mak and N Y Kow This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies Thus the conditionwas traditionally classified as a ldquoB-cell diseaserdquo Compelling evidence has however shown that without the assistance of the helperT lymphocytes it is indeed difficult for the ldquohelplessrdquo B cells to become functional enough to trigger SLE-related inflammationT cells have been recognized to be crucial in the pathogenicity of SLE through their capabilities to communicate with and offerenormous help to B cells for driving autoantibody production Recently a number of phenotypic and functional alterations whichincrease the propensity to trigger lupus-related inflammation have been identified in lupus T cells Here potential mechanismsinvolving alterations in T-cell receptor expressions postreceptor downstream signalling epigenetics and oxidative stress whichfavour activation of lupus T cells will be discussed Additionally how regulatory CD4+ CD8+ and 120574120575 T cells tune down lupus-related inflammation will be highlighted Lastly while currently available outcomes of clinical trials evaluating therapeutic agentswhich manipulate the T cells such as calcineurin inhibitors indicate that they are at least as efficacious and safe as conventionalimmunosuppressants in treating lupus glomerulonephritis larger clinical trials are undoubtedly required to validate these as-yetfavourable findings

1 Introduction

Systemic lupus erythematosus is characterized by the pro-duction of plethora of autoantibodies which potentially driveimmune-complex related inflammation in various tissues andorgans [1] Breakdown of immune tolerance is believed to beone of the major mechanisms which triggers the productionof autoantibodies by B cells and antibody forming cellsleading to inflammation upon binding to autoantigens andconsequent tissue damage [2] As such SLE was classicallythought to be a B-cell driven disease Recent compellingevidence has demonstrated that T cells are actually crucial inthe pathogenesis of SLE in that they enhance the productionof autoantibodies by offering substantial help to B cellsthrough stimulating the latter to differentiate proliferate andmature in addition to their support on class-switching ofautoantibodies which B cells are expressing [3] ThereforeSLE is currently believed to be a T cell-driven condition andindeed targeting molecules expressed on T cells and their

signalling pathways can be one of the potential therapeuticstrategies in SLE

In comparison with healthy subjects a number of studieshave demonstrated that T cells isolated from patients withSLE are abnormal with regard to their phenotypes andfunctions [4 5] Phenotypic and functional alterations inlupus T cells including expansion of the Th17 populationperturbations of the physiology of T-cell receptors (TCRs)andpostreceptor downstream signalling oxidative stress andepigenetic changes result in exaggeration of TCR response tostimuli and the propensity of lupus T cells to get activated [6]Additionally the failure of the regulatory CD4+ and CD8+T lymphocytes in alleviating the proinflammatory milieuoccurring in SLE is contributory to the pathogenicity of thecondition [7 8] In this brief review a detailed account of theputative mechanisms by which the normal physiology of Tcells are disturbed and why regulatory T cells fail to alleviateproinflammatory response in SLE will be discussed Thecurrent state of clinical trials evaluating therapeutic agents

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2014 Article ID 419029 8 pageshttpdxdoiorg1011552014419029

2 Journal of Immunology Research

which target molecules expressing on and inside T cells forthe treatment of SLE will be updated

2 T Cells Their Receptors and Signalling inNormal Situations and SLE

21 T-Cell Receptors and CD3 A Brief Discussion of TheirNormal Structures and Functions T cells recognize antigenspresented to them by the major histocompatibility complexof antigen-presenting cells via the TCRs expressed on theirsurface Stimulation of TCRs upon antigen binding triggersdownstream signalling pathways which enables various phys-iological functions of the T cellsThemajority of TCRs (95)are heterodimers which compose of an 120572 and a 120573 chain (120572120573receptors) and are anchored into the plasma membrane bya short cytoplasmic tail [9] A minor group (15) of TCRscomprise a 120574 and a 120575 chain (120574120575 receptors) which are expressedin certain populations of thymic T cells and peripheral Tcells in the epithelia [10 11] TCRs are associated with CD3which is a series of polypeptides with consistent amino acidsequences and is responsible for signal transduction uponantigen recognition by the TCRs [9 12] CD3 consists offour invariant polypeptides namely 120574 120575 120576 and 120577 and theCD3-TCR complex is arranged in such a way that the fourTCR chains (two 120572 and two 120573 positively charged chains) areassociated with two 120576 two 120577 one 120574 and one 120575 chain polypep-tides of the CD3 which are all negatively charged [9 12] TheCD3 has extracellular transmembrane and cytoplasmic tailswhereby the 2120577 chains (or its variantmdashthe 120578 chain) are thelongest cytoplasmic chains amongst the restThe cytoplasmicportions of 120577 and 120578 chains are critically involved in TCRsignal transduction for they possess the immunoreceptortyrosine-based activation motifs (ITAMs) which are targetsof phosphorylation by various specific protein kinases in thesignal transduction processes [13] Briefly ITAMs becomephosphorylated in a fewminutes following TCR engagementITAMs and the subsequent pathways activated such as the 120577-associated protein 70 (ZAP-70) pathway are essential for T-cell activation [14]

Closely related to CD3120577 Fc120574R also associates with theITAMsHowever instead of stimulating the ZAP-70 pathwaythe spleen tyrosine kinase (Syk) pathway is preferentiallyutilized [15 16] Syk stimulation characteristically results inhigher calcium influx into cells than that involves the ZAP-70 pathway probably regulated by transcription factors c-Junand Ets2 [17] Such ldquorewiringrdquo of postreceptor downstreamsignalling mechanism has a strong pathological implicationin lupus T lymphocytes (discussed in the next section)

22 Alterations in T-Cell Receptors and Their SignallingPathways CD3120577 subunits are suboptimally synthetized inT cells from patients with SLE [18] Moreover reduction ofstability and increase in degradation of CD3120577 in lupus T cellsare evident [19ndash21] To replace the deficient CD3120577 subunitsFcR120574 receptors are reciprocally activated and expressed onlupus T cells [16] Instead of coupling with ZAP-70 forsignalling by the CD3120577 subunits FcR120574 associates with the Sykpathway and such ldquorewiredrdquo downstream signalling confers

stronger phosphorylation of signalling molecules and highercalcium influx which intensifies the TCR-derived signals inlupus T cells [17] Increase in intracellular calcium activatescalcineurin in the cytoplasm which enhances the action ofthe nuclear factor of activated T cells (NF-ATc2) through thedephosphorylating action of calcineurin [22] (See Figure 1)Activated NF-ATc2 alters the expression of certain genesincluding the CD40L gene of lupus T cells by binding to thepromoter of the CD40L gene [22] CD40L is a costimulatorymolecule expressed on T cells and its cognate interactionwith CD40 expressed on B cells promotes differentiationproliferation and antibody production of the latter as well asclass switching in conjunction with the action of IL-10 andIL-21 [23]

Another mechanism whereby lupus T cells exhibit alower threshold of activation is the presence of preaggregatedlipid rafts on their cell membrane [24] The lipid rafts arelipid-rich areas on the cell surface where TCRs and theassociated signalling molecules are concentrated [25 26]During inactivated state lipid rafts are evenly distributedthroughout the cell membrane but in lupus T cells clus-tering of lipid rafts has been demonstrated even whenthey are minimally stimulated [24 27] Clustered lipid raftsenhance lower threshold of signal transduction as moleculesnecessary for receptor activations are physically clusteredin lupus T cells To prove these potential mechanismsintraperitoneal administration of pharmacologically activecompounds which disrupt (M120573CD) and enhance (choleratoxin B) lipid raft clustering demonstrated reduction andpromotion of T-cell activation respectively in a murinelupus-prone model [28]

23 Other Abnormal Signalling Pathways in Lupus T CellsAbnormalities in certain signalling pathways in lupus Tcells which lead to defects in T-cell activation in patientswith SLE have been increasingly identified Impairment ofcyclic adenosine monophosphate (cAMP-)dependent phos-phorylation due to the reduction of protein kinase A levelshas been reported [29 30] In addition the activities ofpathways involving protein kinase C and p56-lymphocyte-specific protein tyrosine kinase (p56lck) have also beenfound to be compromised [31 32] On the other hand theactivities of protein kinase PKR and phosphatidylinositol-3kinase (PI3K) were found to be increased in a lupus-proneanimal model [33 34] Pharmacological inhibition of PI3Kcan ameliorate glomerulonephritis and decrease mortality inthe MRLFaslpr murine lupus model [35] The activity of themitogen-activated protein (MAP) kinases which is crucial inthe proliferation and apoptosis of T cells is reduced in T cellsof patients with SLE [36] Animals which are deficit in PKC(an activator of MAP kinase) have been shown to developspontaneous lupus-like disease [37]

24 Alterations in Gene Expression Partly due to ReducedDNAMethylation As described above upregulation of CD40L inlupus T cells is evident as a result of the activation of NF-ATc2secondary to high calcium flux [17 22] Increase in CD40Lupregulates expressions of CD80 and other costimulatory

Journal of Immunology Research 3

AutoAbs

Y

IL1 IL6 IL17 IL23

YYY

YY

Y

Antilymphocyte Ab

CaMKIV

CREM

IL-2

Calcineurin

NF-ATc2

CD40L

NF-ATc2

PP2A

Elf-1

CREB

CREB

Lipid raftsclustering

Syk

mTOR

Oxidative stress

Tregs

IL6 IL21ICOS

F-ThCostim

ulation

IL-21

B

Naıve T

CD4

DNTC

CD8

IL1120573 TGF120573Reduced IL2

Th17

CD3120577minusP

+P

FcR120574

Elf-1

FcR120574

Ca2+

minusP

minusP

CD4Th17

Figure 1 Development of lupus T cells their interactions with T-regulatory cells and B cells and alterations of the intracellular physiology ofeffector lupus T cells Naıve T cells develop into follicular T-helper cells which cross-talk with B cells for autoantibody production under thestimulation of IL6 IL-21 and ICOS Naıve T cells develop into effector CD4+ and Th17+ T cells which produce proinflammatory cytokinesand exhibit altered intracellular physiology including clustering of CD3-TCR oxidative-stress induced calcium flux and consequent changein mRNA transcriptions of various important genes (see text for details) Abbreviations Tregs regulatory T cells ICOS inducible T-cellcostimulator F-Th follicular T-helper cells Syk spleen tyrosine kinase CaMKIV calciumcalmodulin-dependent kinase IV CREBCREMcAMP response element (CRE) binding protein (CREB)CRE-modulator (CREM) NF-ATc2 nuclear factor of activated T cells Elf-1transcription factor Elf-1 Ca2+ calcium ion PP2A protein phosphatase 2AmTORmitochondrial transmembrane potential andmammaliantarget of rapamycin +P phosphorylation minusP dephosphorylation


molecules on the antigen-presenting cells which furtherintensify the stimulatory signals to the T cells [23] Beinga SLE susceptible gene the CD40L gene is methylationsensitive DNA methylation generally suppresses gene tran-scription and expression In SLE DNA methylation whichhas been shown to be reduced in T cells is linked to Tcell auto-reactivity [23] Hypomethylation in one of the X-chromosomes which is inactive in female lupus patientsinduces overexpression of CD40L mRNA and hence CD40Lexpression on lupus T cells [23] Altered MAP kinase andPKC120575 activities are also caused by hypomethylation sec-ondary to the deficiency of DNAmethyltransferase 1 in lupusT cells [23 38]

IL-2 is essential in reducing the polarization of naıveCD4+ cells towards the Th17 phenotype [39] (see Figure 1)Reduced production of IL-2 demonstrated in patients withSLE enhances the expansion of Th17 population which pro-motes local inflammation and recruitment of immunocytesin part due to the increased production of IL-17 [40]Expression of IL-2 by T cells is in fact tightly regulatedby the transcription factors cAMP response element (CRE)binding protein (CREB) and the CRE-modulator (CREM)[41] CREB enhances the transcription of the IL-2 gene whileCREM suppresses it by competing for the CRE binding sitewith CREB [42] The balance between CREB and CREMactivity which is important in determining whether IL-2 isupregulated or downregulated is altered in lupus T cells [43]The high CREM and CREB ratio in lupus T cells contributesto IL-2 deficiency [43] There are at least 2 proposed mech-anisms to explain the increased CREM and reduced CREBactivities in lupus T cells First high levels of antilymphocyticantibodies in patients with SLE activate calciumcalmodulin-dependent kinase IV (CaMKIV) which enhances CREMactivity through phosphorylation [44] Second the increasedintranuclear level of protein phosphatase 2A (PP2A) in lupusT lymphocytes dephosphorylates and inactivates CREB [4546] One point of note is that Elf-1 an important transcriptionfactor of CD3120577 is dephosphorylated by the increased level ofintranuclear PP2A in lupus T cells [47] DephosphorylatedElf-1 fails to associate with the DNA and initiate transcriptionof CD3120577 transcription leading to the increased FcR120574 andCD3120577 ratio [47] favouring subsequent activation of theSyk instead of ZAP-70 pathways in lupus T cells [17] (seeFigure 1)

Increase in oxidative stress has been demonstrated inlupus lymphocytes as evidenced by ultrastructural changesin the form of tubuloreticular structures of organelles inlymphocytes from patients with active lupus [48] Oxidativestress induces nitric oxide activity and elevation of mito-chondrial transmembrane potential which lead to activationof the protein kinase named mitochondrial transmembranepotential and mammalian target of rapamycin (mTOR) inlupus T cells [49] Increase in mTOR activity causes RAB4A-mediated CD3120577 downregulation and results in high cal-cium flux when lupus T cells are stimulated [50] Increasein intracellular calcium activates cAMP response elementmodulator (CREM) which inhibits IL-2 and enhances IL-17 expressions These changes favour Th1 to Th17 polariza-tion and inhibit CD8+ T cells [51] mTOR activation also

suppresses FoxP3 transcription by inhibiting DNA methyl-transferase 1 (DNMT1) which results in hypomethylation ofthe FoxP3 promoter [51] Rapamycin an inhibitor of mTORwas demonstrated in a small clinical study of nine lupuspatients to be able to normalize T-cell activation-inducedcalcium influx and reduce overall lupus disease activity [50]Other potential mechanisms of mTOR in immune responseinhibition will be discussed in a subsequent section

3 Alteration in the Number and SuppressorActivity of Regulatory T Cells in SLE

31 CD4+ T Regulatory Cells CD4+ regulatory T cells(CD4+ Tregs) were shown to be reduced in the secondarylymphoid organs of theNZBWF1 lupus-pronemousemodelas compared with age-matched nonautoimmune mice [52]Deficiency of CD4+ Tregs is linked to the development oflupus-like disease while adoptive transfer of CD4+ Tregsslowed the progression of renal disease and reduced mor-tality in NZBW F1 mice [52] Besides thymic CD4+ Tregsperipheral-induced CD4+ Tregs (CD4+ iTregs) conferred bythe action of IL-2 and TGF120573 were shown to be able to reduceserum anti-dsDNA levels and alleviate immune complexglomerulonephritis secondary to the reduction of T-cell helpto B cells in NZBW F1 mice [53]

In humans the number of CD4+ Tregs was generallyfound to be lower in patients with active SLE as comparedwith those with inactive disease and healthy individuals [54]Reduced levels of forkhead box P3 (FoxP3) in CD4+ Tregsin patients with active lupus are generally believed to bethe reason why these patients have less Tregs-suppressiveactivity than their counterparts with inactive disease [55ndash57]Interestingly effective immunosuppressive therapies withglucocorticoids and rituximab have been shown to restorethe number of functional Tregs in patients with SLE [58ndash60] Despite the prevailing belief of the inferior quantity andfunctional quality of Tregs in patients with SLE the lack oftruly reliable markers which allow identification and isola-tion of the genuine Treg population renders reliability andreproducibility of Treg studies in SLE an issue [61] Helioswhich is a transcription factor that belongs to the Ikarosfamily has recently been shown to be expressed bymost of theFoxP3+ T-cells in humans and it has been demonstrated to beable to upregulate FoxP3 expression by binding to the FoxP3promoter [62] In contrast to the previous findings whichadvocated the lower quantity of Tregs in lupus patients withmore active disease the population of Foxp3+ Helios+ Tregswas indeed shown to be significantly expanded in patientswith active SLE when compared with those with inactivedisease and healthy controls [61 62] In addition the FoxP3+Helios+ T cells isolated from 20 lupus patients were shown tohave lower IL-2 and IFN120574 productions when compared withthose from FoxP3+ Heliosminus T cells [62]

32 CD8+ T Regulatory Cells In both the NZBW F1 andhuman monoclonal anti-DNA-induced experimental mousemodels expansion of CD8+ Tregs by tolerogenic peptide


suppressed anti-dsDNA production CD4+ T cell prolifera-tion and type-2 interferon production probably as a resultof TGF120573 and FoxP3 produced by the CD8+ iTregs [63 64]

Similar to the findings of CD4+ Tregs studies addressingthe number of circulating CD8+ Tregs in patients withSLE have yielded inconsistent results [65 66] CD8+ Tregsfrom patients with active SLE failed to suppress effector Tcells while CD8+ Tregs from patients with inactive SLEdemonstrated comparable suppressive ability as those fromhealthy individuals [65] Of particular note since the dataof CD8+ Tregs in SLE are based on a small number ofclinical studies more robust studies are required to furthercharacterize the quantity and functional aspects of CD8+Tregs in patients with SLE

33 120574120575 T Regulatory Cells Recently a group of rare 120574120575 T cellswhich express high levels of CD25 and CD27 and low level ofCD45RA has been found to possess regulatory and suppres-sive activities (CD27+CD45RAminus120574120575 Treg cells) particularlythe V1205751 subset [67] Enumeration of the peripheral bloodmononuclear cell (PBMC) populations revealed a signifi-cantly lower number of circulating CD27+CD45RAminus120574120575 Tregcells in patients with SLE as compared to that of healthy con-trols [67] Furthermore a significant inverse correlation wasfound to exist between lupus disease activity and the level ofcirculating CD27+CD45RAminus120574120575Treg cells [67] In vitro exper-iment confirmed the ability of lupusCD27+CD45RAminus120574120575Tregcells to express FoxP3 in a CD27-dependent fashion whenthe cells were cultured in the presence of TGF120573 [67] Inaddition CD27+CD45RAminus120574120575 Treg cells were demonstratedto be able to suppress the proliferation of autologous effectorCD4+ cells in coculture systems [67] Though rare in thePBMC population further experiments are required to fullycharacterize the phenotype and function of these 120574120575Treg cellswhich may play an important immunopathogenic as well aspotential therapeutic roles in suppressing the disease activityof SLE

4 Therapeutic Trials Testing Drugs WhichManipulate T Cells in SLE

41 Calcineurin Inhibitors The most commonly used cal-cineurin inhibitors including cyclosporin and tacrolimushave been proven in randomized controlled trials to be atleast as efficacious and safe as conventional treatment for pro-liferative and membranous lupus glomerulonephritis [68ndash70] A one-year quasirandomized trial revealed proteinuriaremission rates of 83 60 and 27 in patients who werein the cyclosporine intravenous cyclophosphamide andprednisolone groups respectively although the relapse rateof proteinuria was higher in patients receiving cyclosporinethan those who received cyclophosphamide [68] As aninduction therapy the combination of prednisolone andintravenous cyclophosphamide (a total of six 4-week pulsesstarting at 750m2 of body surface area) or tacrolimus(starting at 005mgkgday and being titrated to a troughlevel of 5ndash10 ngmL) has been shown to be equally effica-cious in achieving complete renal remission [70] Tacrolimus

appeared to be safer as adverse events including leucopeniaand gastrointestinal complaints were less frequent as com-pared to subjects in the cyclophosphamide group [70]

42 Anti-CD40L As discussed previously CD40L which isoverexpressed on lupus T cells stimulates CD40 expressed onB cells to produce autoantibodies Antagonization of CD40Lis thus a potential therapeutic target for the treatment ofSLE Two main clinical trials testing the blockade of theCD40-CD40L pathway in the treatment of SLE are howeverdisappointing [71 72] In addition to the failure of satisfyingthe predefined study end-points the unfavourable side-effectprofile of anti-CD40L unfortunately led to the premature ter-mination of amulticentre phase II trial of BG9588 in SLE [72]In a double-blind placebo-controlled trial 85 patients withmild to moderately active SLE were randomized to receive 6infusions of anti-CD40L at doses of 25 5 and 10mgkg andplacebo at 0 2 4 8 12 and 16 weeks [71] After 20 weeks oftreatment lupus disease activity improved in all groups frombaseline but no statistical significance was detected amongstthe different groups [71] No difference in fatigue score andquality of life was noted either [71] In the smaller phaseII open-label trial evaluating BG9588 in the treatment of28 patients with proliferative lupus glomerulonephritis theoccurrence of 2 myocardial infarctions in the subjects ledto premature termination of the trial although significantreduction of proteinuria haematuria and anti-dsDNA titrewith increase in serum C3 levels were demonstrated [72]

43 Rapamycin Being a safe and well-tolerated drug clin-ically used for preventing transplant rejection rapamycina macrolide antibiotic which regulates mitochondrial trans-membrane potential and calcium influx was evaluated in asmall uncontrolled trial for its effectiveness in patients withSLE [50] In 9 lupus patients who were refractory to conven-tional treatment rapamycin 2mg daily reduced the diseaseactivity and prednisolone requirement [50] Mitochondrialcalcium level and T-cell activation-induced calcium fluxingwere normalized in rapamycin-treated patient [50] In arecent prospective open-label study rapamycin was shown toinhibit IL-4 production by and necrosis of double negative(DN) T cells in patients with SLE In addition rapamycinenhanced FoxP3 expression in CD25+CD4+ T-cells andexpansion of CD25+CD19+ B cells [73] signifying thatmTOR can trigger IL-4 production by and necrosis of DN Tcells in active SLE

44 N-Acetylcysteine Recently N-acetylcysteine (NAC) theprecursor of glutathione was shown in a small clinical trialthat at doses 24 gm and 48 gm daily it could reduce lupusdisease activity and fatigue after 3 months of treatment ascompared with placebo [74] NAC reduced mTOR activityand enhanced apoptosis of T cells accompanied by reversedexpansion of the CD4CD8 populations Interestingly NACwas shown to induce FoxP3 expression in CD4+ Treg cellsand reduce serum anti-dsDNA levels [74] Larger clinicaltrials are certainly required to validate the efficacy of thisexciting therapeutic agent especially it is anticipated that


adverse effects of NAC due to immunosuppression are veryminimal

5 Conclusion

In both murine system and human disease of SLE T cellsare found to be abnormal based on their alterations in thephenotype receptor and signalling physiology gene tran-scription and perturbed suppressor activities of regulatorylymphocytes The substantial involvement of T cells in thepathogenesis of SLE and the apparent success in therapeuticsdirecting at T cells in patients with SLE lead to the firmbelief that SLE is indeed a T-cell driven autoimmune diseaseWhile manipulating the B cells and their families withthe use of B-cell depleting therapy (BDT) appears verypromising in the treatment of SLE and it is argued that Bcells are relatively more important in the pathogenesis ofSLE than other immunocytes the discrepantly prolongedbeneficial effects of BDT against the much shorter half-lifeof rituximab invariably explain the potential importance ofthe participation of T cells in the pathogenic process of SLE[58 59]

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] Z Liu and A Davidson ldquoBAFF and selection of autoreactive Bcellsrdquo Trends in Immunology vol 32 no 8 pp 388ndash394 2011

[3] M J Shlomchik J E Craft andM JMamula ldquoFromT to B andback again positive feedback in systemic autoimmune diseaserdquoNature Reviews Immunology vol 1 no 2 pp 147ndash153 2001

[4] V R Moulton and G C Tsokos ldquoAbnormalities of T cellsignaling in systemic lupus erythematosusrdquo Arthritis ResearchandTherapy vol 13 no 2 article 207 2011

[5] J C Crispın V C Kyttaris Y-T Juang and G C TsokosldquoHow signaling and gene transcription aberrations dictate thesystemic lupus erythematosus T cell phenotyperdquo Trends inImmunology vol 29 no 3 pp 110ndash115 2008

[6] J C Crispın and G C Tsokos ldquoT cellsrdquo in Duboisrsquo LupusErythematosus and Related Syndromes D J Wallace and B HHahn Eds pp 96ndash103 Elvesier AmsterdamThe Netherlands8th edition 2013

[7] P Sawla A Hossain B H Hahn and R P Singh ldquoRegulatoryT cells in systemic lupus erythematosus (SLE) Role of peptidetolerancerdquo Autoimmunity Reviews vol 11 no 9 pp 611ndash6142012

[8] R K Dinesh B J Skaggs A La Cava B H Hahn and RP Singh ldquoCD8+ Tregs in lupus autoimmunity and beyondrdquoAutoimmunity Reviews vol 9 no 8 pp 560ndash568 2010

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[10] A C Hayday ldquo120574120575 cells a right time and a right place for a con-served third way of protectionrdquo Annual Review of Immunologyvol 18 pp 975ndash1026 2000

[11] Y H Chien R Jores and M P Crowley ldquoRecognition bygammadelta T cellsrdquoAnnual Review of Immunology vol 14 pp511ndash532 1996

[12] E S Jose A G Sahuquillo R Bragado and B AlarconldquoAssembly of the TCRCD3 complex CD3 epsilondelta andCD3 epsilongamma dimers associate indistinctly with bothTCR alpha and TCR beta chains Evidence for a double TCRheterodimer modelrdquo European Journal of Immunology vol 28no 1 pp 12ndash21 1998

[13] AWeiss andD R Littman ldquoSignal transduction by lymphocyteantigen receptorsrdquo Cell vol 76 no 2 pp 263ndash274 1994

[14] S Deindl T A Kadlecek T Brdicka X Cao A Weiss and JKuriyan ldquoStructural basis for the inhibition of tyrosine kinaseactivity of ZAP-70rdquo Cell vol 129 no 4 pp 735ndash746 2007

[15] S Krishnan Y-T Juang B Chowdhury et al ldquoDifferentialexpression and molecular associations of Syk in systemic lupuserythematosus T cellsrdquo Journal of Immunology vol 181 no 11pp 8145ndash8152 2008

[16] E J Enyedy M P Nambiar S N Liossis G Dennis G MKammer and G C Tsokos ldquoFc epsilon receptor type I gammachain replaces the deficient T cell receptor zeta chain in Tcells of patients with systemic lupus erythematosusrdquo Arthritisamp Rheumatology vol 44 no 5 pp 1114ndash1121 2001

[17] D Ghosh G C Tsokos and V C Kyttaris ldquoC-Jun and Ets2proteins regulate expression of spleen tyrosine kinase in T cellsrdquoJournal of Biological Chemistry vol 287 no 15 pp 11833ndash118412012

[18] S N Liossis X Z Ding G J Dennis andG C Tsokos ldquoAlteredpattern of TCRCD3-mediated protein-tyrosyl phosphoryla-tion in T cells from patients with systemic lupus erythematosusDeficient expression of the T cell receptor zeta chainrdquo TheJournal of Clinical Investigation vol 101 no 7 pp 1448ndash14571998

[19] S Krishnan J G Kiang C U Fisher et al ldquoIncreased caspase-3expression and activity contribute to reduced CD3120577 expressionin systemic lupus erythematosus T cellsrdquo Journal of Immunol-ogy vol 175 no 5 pp 3417ndash3423 2005

[20] V R Moulton V C Kyttaris Y-T Juang B Chowdhury andG C Tsokos ldquoThe RNA-stabilizing protein HuR regulates theexpression of 120577 chain of the human T cell receptor-associatedCD3 complexrdquo Journal of Biological Chemistry vol 283 no 29pp 20037ndash20044 2008

[21] B Chowdhury C G Tsokos S Krishnan et al ldquoDecreasedstability and translation of T cell receptor 120577 mRNA with analternatively spliced 31015840-untranslated region contribute to 120577chain down-regulation in patients with systemic lupus erythe-matosusrdquo Journal of Biological Chemistry vol 280 no 19 pp18959ndash18966 2005

[22] V C Kyttaris Y Wang Y-T Juang A Weinstein and GC Tsokos ldquoIncreased levels of NF-ATc2 differentially regulateCD154 and IL-2 genes in T cells from patients with systemiclupus erythematosusrdquo Journal of Immunology vol 178 no 3 pp1960ndash1966 2007

[23] N Y Kow and A Mak ldquoCostimulatory pathways physiologyand potential therapeutic manipulation in systemic lupus ery-thematosusrdquoClinical andDevelopmental Immunology vol 2013Article ID 245928 12 pages 2013

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[25] PW Janes S C Ley and A I Magee ldquoAggregation of lipid raftsaccompanies signaling via the T cell antigen receptorrdquo Journalof Cell Biology vol 147 no 2 pp 447ndash461 1999

[26] P W Janes S C Ley A I Magee and P S Kabouridis ldquoTherole of lipid rafts in T cell antigen receptor (TCR) signallingrdquoSeminars in Immunology vol 12 no 1 pp 23ndash34 2000

[27] S Krishnan M P Nambiar V G Warke et al ldquoAlterations inlipid raft composition and dynamics contribute to abnormalT cell responses in systemic lupus erythematosusrdquo Journal ofImmunology vol 172 no 12 pp 7821ndash7831 2004

[28] G M Deng and G C Tsokos ldquoCholera toxin B acceleratesdisease progression in lupus-pronemice by promoting lipid raftaggregationrdquo Journal of Immunology vol 181 no 6 pp 4019ndash4026 2008

[29] G M Kammer I U Khan and C J Malemud ldquoDeficienttype I protein kinase A isozyme activity in systemic lupuserythematosus T lymphocytesrdquo Journal of Clinical Investigationvol 94 no 1 pp 422ndash430 1994

[30] R Mandler R E Birch and S H Polmar ldquoAbnormaladenosine-induced immunosuppression and cAMPmetabolism in T lymphocytes of patients with systemiclupus erythematosusrdquo Proceedings of the National Academy ofSciences of the United States of America I vol 79 no 23 pp7542ndash7546 1982

[31] Y Tada K Nagasawa Y Yamauchi H Tsukamoto and Y NiholdquoA defect in the protein kinase C system in T cells from patientswith systemic lupus erythematosusrdquo Clinical Immunology andImmunopathology vol 60 no 2 pp 220ndash231 1991

[32] C Matache M Stefanescu A Onu et al ldquop56(lck) activity andexpression in peripheral blood lymphocytes from patients withsystemic lupus erythematosusrdquoAutoimmunity vol 29 no 2 pp111ndash120 1999

[33] F Niculescu P Nguyen T Niculescu H Rus V Rus and CS Via ldquoPathogenic T cells in murine lupus exhibit sponta-neous signaling activity through phosphatidylinositol 3-kinaseand mitogen-activated protein kinase pathwaysrdquo Arthritis andRheumatism vol 48 no 4 pp 1071ndash1079 2003

[34] A Grolleau M J Kaplan S M Hanash L Beretta and BRichardson ldquoImpaired translational response and increasedprotein kinase PKR expression in T cells from lupus patientsrdquoJournal of Clinical Investigation vol 106 no 12 pp 1561ndash15682000

[35] D F Barber A Bartolome C Hernandez et al ldquoPI3K120574inhibition blocks glomerulonephritis and extends lifespan in amouse model of systemic lupusrdquo Nature Medicine vol 11 no 9pp 933ndash935 2005

[36] S Cedeno D F Cifarelli A M Blasini et al ldquoDefective activityof ERK-1 and ERK-2 mitogen-activated protein kinases inperipheral blood T lymphocytes from patients with systemiclupus erythematosus potential role of altered coupling of Rasguanine nucleotide exchange factor hSos to adapter proteinGrb2 in lupus T cellsrdquo Clinical Immunology vol 106 no 1 pp41ndash49 2003

[37] G Gorelik Y F Jing A Wu A H Sawalha and B Richard-son ldquoImpaired T cell protein kinase C120575 activation decreasesERK pathway signaling in idiopathic and hydralazine-inducedlupusrdquo Journal of Immunology vol 179 no 8 pp 5553ndash55632007

[38] A H Sawalha andM Jeffries ldquoDefective DNAmethylation andCD70 overexpression in CD4+ T cells in MRLlpr lupus-pronemicerdquo European Journal of Immunology vol 37 no 5 pp 1407ndash1413 2007

[39] J Alcocer-Varela and D Alarcon-Segovia ldquoDecreased produc-tion of and response to interleukin-2 by cultured lymphocytesfrom patients with systemic lupus erythematosusrdquo Journal ofClinical Investigation vol 69 no 6 pp 1388ndash1392 1982

[40] J C Crispın M Oukka G Bayliss et al ldquoExpanded doublenegative T cells in patients with systemic lupus erythematosusproduce IL-17 and infiltrate the kidneysrdquo Journal of Immunol-ogy vol 181 no 12 pp 8761ndash8766 2008

[41] K Tenbrock and G C Tsokos ldquoTranscriptional regulation ofinterlekin 2 in SLE T cellsrdquo International Reviews of Immunol-ogy vol 23 no 3-4 pp 333ndash345 2004

[42] D Gomez-Martın M Dıaz-Zamudio J C Crispın and JAlcocer-Varela ldquoInterleukin 2 and systemic lupus erythemato-sus beyond the transcriptional regulatory net abnormalitiesrdquoAutoimmunity Reviews vol 9 no 1 pp 34ndash39 2009

[43] E E Solomou Y-T Juang M F Gourley G M Kammer andG C Tsokos ldquoMolecular basis of deficient IL-2 production in Tcells from patients with systemic lupus erythematosusrdquo Journalof Immunology vol 166 no 6 pp 4216ndash4222 2001

[44] Y-T Juang Y Wang E E Solomou et al ldquoSystemic lupuserythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIVrdquoJournal of Clinical Investigation vol 115 no 4 pp 996ndash10052005

[45] B E Wadzinski W H Wheat S Jaspers et al ldquoNuclearprotein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptionalstimulationrdquo Molecular and Cellular Biology vol 13 no 5 pp2822ndash2834 1993

[46] C G Katsiari V C Kyttaris Y-T Juang andG C Tsokos ldquoPro-tein phosphatase 2A is a negative regulator of IL-2 production inpatients with systemic lupus erythematosusrdquo Journal of ClinicalInvestigation vol 115 no 11 pp 3193ndash3204 2005

[47] Y-T Juang Y Wang G Jiang et al ldquoPP2A dephosphory-lates Elf-1 and determines the expression of CD3120577 and FcR120574in human systemic lupus erythematosus T cellsrdquo Journal ofImmunology vol 181 no 5 pp 3658ndash3664 2008

[48] A Mak Z A Almsherqi Y W Lai A A Cheak and Y DengldquoIntracellular tubulo-reticular structures of peripheral bloodmononuclear cells as an ultra-structuralmarker of disease activ-ity in systemic lupus erythematosus a pilot studyrdquo InternationalJournal of the Rheumatic Diseases vol 16 no 6 pp 692ndash6972013

[49] G Nagy M Barcza N Gonchoroff P E Phillips and A PerlldquoNitric oxide-dependent mitochondrial biogenesis generatesCa2+ signaling profile of lupus T cellsrdquo Journal of Immunologyvol 173 no 6 pp 3676ndash3683 2004

[50] D Fernandez E Bonilla N Mirza B Niland and A PerlldquoRapamycin reduces disease activity and normalizes T cellactivation-induced calcium fluxing in patients with systemiclupus erythematosusrdquo Arthritis and Rheumatism vol 54 no 9pp 2983ndash2988 2006

[51] A Perl ldquoOxidative stress in the pathology and treatment ofsystemic lupus erythematosusrdquo Nature Reviews Rheumatologyvol 9 no 11 pp 674ndash686 2013

[52] K J Scalapino Q Tang J A Bluestone M L Bonyhadi andD I Daikh ldquoSuppression of disease in New Zealand BlackNew


Zealand white lupus-prone mice by adoptive transfer of ex vivoexpanded regulatory T cellsrdquo Journal of Immunology vol 177no 3 pp 1451ndash1459 2006

[53] A La Cava F M Ebling and B H Hahn ldquoIg-reactiveCD4+CD25+ T cells from toterized (New Zealand black timesNew Zealand white)F1 mice suppress in vitro production ofantibodies to DNArdquo Journal of Immunology vol 173 no 5 pp3542ndash3548 2004

[54] A La Cava ldquoT-regulatory cells in systemic lupus erythemato-susrdquo Lupus vol 17 no 5 pp 421ndash425 2008

[55] M Miyara Z Amoura C Parizot et al ldquoGlobal natural regu-latory T cell depletion in active systemic lupus erythematosusrdquoJournal of Immunology vol 175 no 12 pp 8392ndash8400 2005

[56] E Y Lyssuk A V Torgashina S K Soloviev E L Nassonovand S N Bykovskaia ldquoReduced number and function ofCD4+CD25 high FoxP3+ regulatory T cells in patients with sys-temic lupus erythematosusrdquoAdvances in ExperimentalMedicineand Biology vol 601 pp 113ndash119 2007

[57] X Valencia C Yarboro G Illei and P E Lipsky ldquoDeficientCD4+CD25high T regulatory cell function in patients withactive systemic lupus erythematosusrdquo Journal of Immunologyvol 178 no 4 pp 2579ndash2588 2007

[58] P P Sfikakis V L Souliotis K G Fragiadaki H M Mout-sopoulos J N Boletis and A N Theofilopoulos ldquoIncreasedexpression of the FoxP3 functional marker of regulatory T cellsfollowing B cell depletion with rituximab in patients with lupusnephritisrdquo Clinical Immunology vol 123 no 1 pp 66ndash73 2007

[59] M Vigna-Perez B Hernandez-Castro O Paredes-Saharopuloset al ldquoClinical and immunological effects of Rituximab inpatients with lupus nephritis refractory to conventional ther-apy a pilot studyrdquo Arthritis Research and Therapy vol 8 no 3article R83 2006

[60] A-M Cepika I Marinic J Morovic-Vergles D Soldo-Juresaand A Gagro ldquoEffect of steroids on the frequency of regulatoryT Cells and expression of FoxP3 in a patient with systemic lupuserythematosus a two-year follow-uprdquo Lupus vol 16 no 5 pp374ndash377 2007

[61] A Golding S Hasni G Illei and E M Shevach ldquoThepercentage of FoxP3+Helios+ Treg cells correlates positivelywith disease activity in systemic lupus erythematosusrdquoArthritisRheum vol 65 no 11 pp 2898ndash2906 2013

[62] T Alexander A Sattler L Templin et al ldquoFoxp3+ Helios+regulatory T cells are expanded in active systemic lupus erythe-matosusrdquo Annals of the Rheumatic Diseases vol 72 no 9 pp1549ndash1558 2013

[63] R P Singh A la Cava and B H Hahn ldquopConsensus peptideinduces tolerogenic CD8+ T cells in lupus-prone (NZB timesNZW)F1 mice by differentially regulating Foxp3 and PD1moleculesrdquo Journal of Immunology vol 180 no 4 pp 2069ndash2080 2008

[64] E Eilat M Dayan H Zinger and E Mozes ldquoThe mechanismby which a peptide based on complementarity-determiningregion-1 of a pathogenic anti-DNA auto-Ab ameliorates exper-imental systemic lupus erythematosusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 98 no 3 pp 1148ndash1153 2001

[65] G Filaci S Bacilieri M Fravega et al ldquoImpairment of CD8+ Tsuppressor cell function in patients with active systemic lupuserythematosusrdquo Journal of Immunology vol 166 no 10 pp6452ndash6457 2001

[66] B Alvarado-Sanchez B Hernandez-Castro D Portales-Perezet al ldquoRegulatory T cells in patients with systemic lupus

erythematosusrdquo Journal of Autoimmunity vol 27 no 2 pp 110ndash118 2006

[67] X Li N Kang X Zhang et al ldquoGeneration of human regulatory120574120575 T cells by TCR120574120575 stimulation in the presence of TGF-120573and their involvement in the pathogenesis of systemic lupuserythematosusrdquo Journal of Immunology vol 186 no 12 pp6693ndash6700 2011

[68] H A Austin III G G Illei M J Braun and J E Balow ldquoRan-domized controlled trial of prednisone cyclophosphamideand cyclosporine in lupus membranous nephropathyrdquo Journalof the American Society of Nephrology vol 20 no 4 pp 901ndash911 2009

[69] G Moroni A Doria M Mosca et al ldquoA randomized pilottrial comparing cyclosporine and azathioprine for maintenancetherapy in diffuse lupus nephritis over four yearsrdquo ClinicalJournal of the American Society of Nephrology CJASN vol 1 no5 pp 925ndash932 2006

[70] W Chen X Tang Q Liu et al ldquoShort-term outcomes ofinduction therapy with tacrolimus versus cyclophosphamidefor active lupus nephritis a multicenter randomized clinicaltrialrdquo The American Journal of Kidney Diseases vol 57 no 2pp 235ndash244 2011

[71] K C Kalunian J C Davis Jr J T Merrill M C Totoritisand D Wofsy ldquoTreatment of systemic lupus erythematosusby inhibition of T cell costimulation with anti-CD154 a ran-domized double-blind placebo-controlled trialrdquo Arthritis andRheumatism vol 46 no 12 pp 3251ndash3258 2002

[72] D T Boumpas R Furie S Manzi et al ldquoA short courseof BG9588 (anti-CD40 ligand antibody) improves serologicactivity and decreases hematuria in patients with proliferativelupus glomerulonephritisrdquo Arthritis and Rheumatism vol 48no 3 pp 719ndash727 2003

[73] Z W Lai R Borsuk A Shadakshari et al ldquoMechanistic targetof rapamycin activation triggers IL-4 production and necroticdeath of double-negative T cells in patients with systemic lupuserythematosusrdquo The Journal of Immunology vol 191 no 5 pp2236ndash2246 2013

[74] Z W Lai R Hanczko E Bonilla et al ldquoN-acetylcysteinereduces disease activity by blocking mammalian target ofrapamycin in T cells from systemic lupus erythematosuspatients a randomized double-blind placebo-controlled trialrdquoArthritis amp Rheumatology vol 64 no 9 pp 2937ndash2946 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


which target molecules expressing on and inside T cells forthe treatment of SLE will be updated

2 T Cells Their Receptors and Signalling inNormal Situations and SLE

21 T-Cell Receptors and CD3 A Brief Discussion of TheirNormal Structures and Functions T cells recognize antigenspresented to them by the major histocompatibility complexof antigen-presenting cells via the TCRs expressed on theirsurface Stimulation of TCRs upon antigen binding triggersdownstream signalling pathways which enables various phys-iological functions of the T cellsThemajority of TCRs (95)are heterodimers which compose of an 120572 and a 120573 chain (120572120573receptors) and are anchored into the plasma membrane bya short cytoplasmic tail [9] A minor group (15) of TCRscomprise a 120574 and a 120575 chain (120574120575 receptors) which are expressedin certain populations of thymic T cells and peripheral Tcells in the epithelia [10 11] TCRs are associated with CD3which is a series of polypeptides with consistent amino acidsequences and is responsible for signal transduction uponantigen recognition by the TCRs [9 12] CD3 consists offour invariant polypeptides namely 120574 120575 120576 and 120577 and theCD3-TCR complex is arranged in such a way that the fourTCR chains (two 120572 and two 120573 positively charged chains) areassociated with two 120576 two 120577 one 120574 and one 120575 chain polypep-tides of the CD3 which are all negatively charged [9 12] TheCD3 has extracellular transmembrane and cytoplasmic tailswhereby the 2120577 chains (or its variantmdashthe 120578 chain) are thelongest cytoplasmic chains amongst the restThe cytoplasmicportions of 120577 and 120578 chains are critically involved in TCRsignal transduction for they possess the immunoreceptortyrosine-based activation motifs (ITAMs) which are targetsof phosphorylation by various specific protein kinases in thesignal transduction processes [13] Briefly ITAMs becomephosphorylated in a fewminutes following TCR engagementITAMs and the subsequent pathways activated such as the 120577-associated protein 70 (ZAP-70) pathway are essential for T-cell activation [14]

Closely related to CD3120577 Fc120574R also associates with theITAMsHowever instead of stimulating the ZAP-70 pathwaythe spleen tyrosine kinase (Syk) pathway is preferentiallyutilized [15 16] Syk stimulation characteristically results inhigher calcium influx into cells than that involves the ZAP-70 pathway probably regulated by transcription factors c-Junand Ets2 [17] Such ldquorewiringrdquo of postreceptor downstreamsignalling mechanism has a strong pathological implicationin lupus T lymphocytes (discussed in the next section)

22 Alterations in T-Cell Receptors and Their SignallingPathways CD3120577 subunits are suboptimally synthetized inT cells from patients with SLE [18] Moreover reduction ofstability and increase in degradation of CD3120577 in lupus T cellsare evident [19ndash21] To replace the deficient CD3120577 subunitsFcR120574 receptors are reciprocally activated and expressed onlupus T cells [16] Instead of coupling with ZAP-70 forsignalling by the CD3120577 subunits FcR120574 associates with the Sykpathway and such ldquorewiredrdquo downstream signalling confers

stronger phosphorylation of signalling molecules and highercalcium influx which intensifies the TCR-derived signals inlupus T cells [17] Increase in intracellular calcium activatescalcineurin in the cytoplasm which enhances the action ofthe nuclear factor of activated T cells (NF-ATc2) through thedephosphorylating action of calcineurin [22] (See Figure 1)Activated NF-ATc2 alters the expression of certain genesincluding the CD40L gene of lupus T cells by binding to thepromoter of the CD40L gene [22] CD40L is a costimulatorymolecule expressed on T cells and its cognate interactionwith CD40 expressed on B cells promotes differentiationproliferation and antibody production of the latter as well asclass switching in conjunction with the action of IL-10 andIL-21 [23]

Another mechanism whereby lupus T cells exhibit alower threshold of activation is the presence of preaggregatedlipid rafts on their cell membrane [24] The lipid rafts arelipid-rich areas on the cell surface where TCRs and theassociated signalling molecules are concentrated [25 26]During inactivated state lipid rafts are evenly distributedthroughout the cell membrane but in lupus T cells clus-tering of lipid rafts has been demonstrated even whenthey are minimally stimulated [24 27] Clustered lipid raftsenhance lower threshold of signal transduction as moleculesnecessary for receptor activations are physically clusteredin lupus T cells To prove these potential mechanismsintraperitoneal administration of pharmacologically activecompounds which disrupt (M120573CD) and enhance (choleratoxin B) lipid raft clustering demonstrated reduction andpromotion of T-cell activation respectively in a murinelupus-prone model [28]

23 Other Abnormal Signalling Pathways in Lupus T CellsAbnormalities in certain signalling pathways in lupus Tcells which lead to defects in T-cell activation in patientswith SLE have been increasingly identified Impairment ofcyclic adenosine monophosphate (cAMP-)dependent phos-phorylation due to the reduction of protein kinase A levelshas been reported [29 30] In addition the activities ofpathways involving protein kinase C and p56-lymphocyte-specific protein tyrosine kinase (p56lck) have also beenfound to be compromised [31 32] On the other hand theactivities of protein kinase PKR and phosphatidylinositol-3kinase (PI3K) were found to be increased in a lupus-proneanimal model [33 34] Pharmacological inhibition of PI3Kcan ameliorate glomerulonephritis and decrease mortality inthe MRLFaslpr murine lupus model [35] The activity of themitogen-activated protein (MAP) kinases which is crucial inthe proliferation and apoptosis of T cells is reduced in T cellsof patients with SLE [36] Animals which are deficit in PKC(an activator of MAP kinase) have been shown to developspontaneous lupus-like disease [37]

24 Alterations in Gene Expression Partly due to ReducedDNAMethylation As described above upregulation of CD40L inlupus T cells is evident as a result of the activation of NF-ATc2secondary to high calcium flux [17 22] Increase in CD40Lupregulates expressions of CD80 and other costimulatory


AutoAbs

Y

IL1 IL6 IL17 IL23

YYY

YY

Y

Antilymphocyte Ab

CaMKIV

CREM

IL-2

Calcineurin

NF-ATc2

CD40L

NF-ATc2

PP2A

Elf-1

CREB

CREB


Syk

mTOR

Oxidative stress

Tregs

IL6 IL21ICOS

F-ThCostim

ulation

IL-21

B

Naıve T

CD4

DNTC

CD8


Th17

CD3120577minusP

+P

FcR120574

Elf-1

FcR120574

Ca2+

minusP

minusP

CD4Th17























5 Conclusion




References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















AutoAbs

Y

IL1 IL6 IL17 IL23

YYY

YY

Y

Antilymphocyte Ab

CaMKIV

CREM

IL-2

Calcineurin

NF-ATc2

CD40L

NF-ATc2

PP2A

Elf-1

CREB

CREB


Syk

mTOR

Oxidative stress

Tregs

IL6 IL21ICOS

F-ThCostim

ulation

IL-21

B

Naıve T

CD4

DNTC

CD8


Th17

CD3120577minusP

+P

FcR120574

Elf-1

FcR120574

Ca2+

minusP

minusP

CD4Th17























5 Conclusion




References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































5 Conclusion




References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























5 Conclusion




References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 Conclusion




References





















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article The Pathology of T Cells in Systemic Lupus ...downloads.hindawi.com/journals/jir/2014/419029.pdf · The Pathology of T Cells in Systemic Lupus Erythematosus AnselmMak

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