Mireia Sospedra and Roland Martin - Semantic Scholar...Mireia Sospedra and Roland Martin Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders

10 Dec 2004 22:8 AR AR239-IY23-21.tex XMLPublishSM(2004/02/24) P1: JRXAR REVIEWS IN ADVANCE10.1146/annurev.immunol.23.021704.115707

(Some corrections may occur before final publication online and in print)

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E Annu. Rev. Immunol. 2005. 23:683–747doi: 10.1146/annurev.immunol.23.021704.115707

Copyright c© 2005 by Annual Reviews. All rights reserved

IMMUNOLOGY OF MULTIPLE SCLEROSIS∗

Mireia Sospedra and Roland MartinCellular Immunology Section, Neuroimmunology Branch, National Institute ofNeurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland20892-1400; email: [email protected]; [email protected]

Key Words autoimmunity, autoimmune mechanisms, neuroimmunology,demyelinating dieseases, EAE

■ Abstract Multiple sclerosis (MS) develops in young adults with a complex pre-disposing genetic trait and probably requires an inciting environmental insult such asa viral infection to trigger the disease. The activation of CD4+ autoreactive T cellsand their differentiation into a Th1 phenotype is a crucial event in the initial steps,and these cells are probably also important players in the long-term evolution of thedisease. Damage of the target tissue, the central nervous system, is, however, mostlikely mediated by other components of the immune system, such as antibodies, com-plement, CD8+ T cells, and factors produced by innate immune cells. Perturbationsin immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NKcells, and others may in part be responsible for the relapsing-remitting or chronic pro-gressive nature of the disease. However, an important paradigmatic shift in the studyof MS has occurred in the past decade. It is now clear that MS is not just a diseaseof the immune system, but that factors contributed by the central nervous system areequally important and must be considered in the future.

INTRODUCTION

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervoussystem (CNS), i.e., the brain and spinal cord, and usually starts between 20 and40 years of age (1, 2).1,2 At least 350,000 individuals in the United States alone areaffected with MS. It leads to substantial disability through deficits of sensation andof motor, autonomic, and neurocognitive function. The disease is usually not life

∗The U.S. Government has the right to retain a nonexclusive, royalty-free license in and toany copyright covering this paper.1Owing to space restrictions, additional references for each section of this review are ac-cessible in the Supplementary Material. Follow the Supplemental Material link from theAnnual Reviews home page at http://www.annualreviews.org.2See Appendix for a full list of abbreviations used.

0732-0582/05/0423-0683$14.00 683

First published online as a Review in Advance on January 19, 2005

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684 SOSPEDRA � MARTIN

shortening, but its socioeconomic importance is second only to trauma in youngadults (1, 2). There are two major forms of MS. Relapsing-remitting (RR)-MS isthe most frequent (85%–90%) and affects women about twice as often as men.Most RR-MS patients later develop secondary progressive (SP)-MS (Figure 1).About 10%–15% of patients present with insidious disease onset and steady pro-gression, termed primary progressive (PP)-MS. It is not clear which factors areresponsible for the different courses. There is also heterogeneity in morphologicalalterations of the brain by magnetic resonance imaging (MRI) (3) or histopatho-logical evaluation (4, 5), as well as in clinical presentation, e.g., which CNS systemand areas are primarily affected and whether a patient responds to treatment. Thefactors underlying this heterogeneity are not completely understood but includea complex genetic trait that translates into different immune abnormalities and/orincreased vulnerability of CNS tissue to inflammatory insult or reduced ability torepair damage (Figure 1).

MS is still considered a CD4+ Th1-mediated autoimmune disease (6, 7). Thisview is based on the cellular composition of brain- and cerebrospinal fluid(CSF)-infiltrating cells and data from experimental allergic (autoimmune) en-cephalomyelitis (EAE) (8). In the EAE model, the injection of myelin componentsinto susceptible animals leads to a CD4+-mediated autoimmune disease that sharessimilarities with MS (6, 8) and can be adoptively transferred by encephalitogenicCD4+ T cells into a naive animal (6, 8, 9). EAE cannot be transferred by antibod-ies, and so far it has been transferred in only two instances by CD8+ T cells (10,11), emphasizing the importance of CD4+ T cells. The role of CD4+ T cells in MSis supported by many parallels with EAE, but it is also supported indirectly by thefact that certain HLA class II molecules represent the strongest genetic risk factorfor MS, presumably via their role as antigen-presenting molecules to pathogenicCD4+ T cells.

The above considerations still apply, but research during the past decade hasnot only substantially increased our knowledge of the involvement of CD4+

T cells in MS but also shown that the previous concepts were too simplistic anddid not appropriately consider immune factors other than CD4+ T cells. Anotheraspect might turn out to be even more important. We have for a long time almostcompletely ignored the contribution of the affected organ, the CNS. Pathologicand imaging studies (3, 5), as well as research of the molecular aspects of thedisease in EAE and MS, now provide ample evidence that CNS-specific factorsare important (12, 13). In this context, it is interesting, although historically nottoo surprising, that reviews on organ-specific autoimmune diseases, such as type1 diabetes or rheumatoid arthritis, focus entirely on alterations of tolerance, spe-cific immune cells, and other immune aspects, but rarely on the involvement offactors intrinsic to the target tissue. For MS, such an “immune-centered” viewcan not be upheld, and consequently in this chapter we deviate from our previousreview 12 years ago (6) and consider the role of the CNS in targeting the dis-ease process, in interactions with the immune system, and in the long-term courseof MS.

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IMMUNOLOGY OF MULTIPLE SCLEROSIS 685

Figure 1 Top: Schematic depiction of the clinical evolution of MS by a clinical scale(EDSS, red line); the frequency of inflammatory events when studied by MRI (T1lesions with contrast showing blood-brain barrier opening, blue arrows); T2 lesionload documenting all tissue damage (blue line); brain atrophy (green line). Pathology:Main pathological characteristics of MS. On the left, perivascular inflammation withmononuclear cells and open blood-brain barrier (courtesy of H.F. McFarland, NIB,NINDS, NIH); on the right, demyelinated areas shown in light blue and white, and,on the far right, axonal transactions (blue onion bulb-like structure) and segmentaldemyelination (from Reference 339, with kind permission of N. Engl. J. Med.). MRI:Typical MRI characteristics. On the left, T1-weighted image with Gadolinium contrastenhancement. White lesions indicate areas of fresh inflammation and open blood-brainbarrier. T2-weighted image shows the CSF-filled ventricles in white and MS lesions inthe brain parenchyma. On the right, brain atrophy with widened lateral ventricles andcortical sulci.

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ETIOLOGY OF MS: IMMUNOGENETIC BACKGROUND

The etiology of MS remains unclear, but according to current data the diseasedevelops in genetically susceptible individuals and may require additional envi-ronmental triggers. Virtually hundreds of studies in the past decades have addressedthe genetic contribution, and for details the reader is referred to excellent reviewsand the original articles (14, 15). Here, we try to distill from the existing literaturethe most relevant aspects in the context of the immunopathogenesis of MS.

The general population prevalence of MS varies between 60–200/100,000 inNorthern Europe and North America, and 6–20/100,000 in low risk areas such asJapan. Population, family, and twin studies all show that the prevalence is sub-stantially increased in family members of MS patients (14). First-degree relativesof affected individuals have an approximately 20- to 50-fold (2%–5%) higher riskto develop MS, and concordance rates in monozygotic twins vary between 20%and 35% in different studies, with the most recent studies placing it at 25% (14).Although the modest concordance rate has been viewed as a sign of environmentalinfluences, studies of adoptees in MS families (16) and other data indicate that thegenetic risk is probably higher. The search for individual susceptibility genes hasso far been frustrating, despite tremendous advances. More than 20 whole genomescreens have been performed in different MS populations and different geographicareas, with up to 6000 microsatellite markers and different methodologies (17).The data are strongest for one or more susceptibility genes on chromosome 6p21in the area of the major histocompatibility complex [MHC; histocompatibilityleukocyte antigen (HLA) in humans], which is thought to account for 10%–60%of the genetic risk of MS (18, 19).

THE ROLE OF THE HLA GENE COMPLEX

Similar to other T cell–mediated autoimmune diseases, in MS the specific genesthat confer risk are the HLA-DR and -DQ genes, the HLA-DR15 haplotype inCaucasians (DRB1∗1501, DRB5∗0101, DQA1∗0102, DQB1∗0602) (18), but alsoother DRs in ethnically more distant populations. Most of the risk stems from thetwo DR alleles that are in very tight linkage disequilibrium, and there is also a doseeffect in DR15 homozygotic MS patients (20). The contribution of DQA1∗0102/-B1∗0602 varies, and both additive and independent effects have been described,particularly in populations with lower overall MS prevalence (21, 22). AdditionalMS “risk/protective alleles” are listed in Table 1. Less information exists regardinggenetic risk conferred by HLA class I alleles. Their association with MS appearsto be much lower. HLA-A3 and -B7 are overrepresented in MS patients, and HLA-A201 has shown protective effects (18, 21, 23) (Table 1). With respect to associa-tions of HLA-DR/DQ alleles with other genes, or clinical, MRI, or immunologicalcharacteristics, only limited data are available (Table 2). Genes associated with theDR15 haplotype include transforming growth factor (TGF)-β family members,

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TABLE 1 Association of HLA class I and class II alleles with multiple sclerosis

MHC class I/II alleleEthnic background/populationand geographic location/country

MS subtypeassociation Remark

DRB1∗1501 Caucasians, many countries andbackgrounds including Japanese,Tasmanians, and many others

All subtypes Independent and joint with DQ;dose effect

DRB1∗1503 Martinique None —

DRB1∗1506, -1508 India None Joint with ∗1501

DRB1∗15/DR3 Mexican Mestizos None —

DRB1∗0301 Sardinia None —

DRB1∗03/A30/B18 Central Sardinia None —

DRB1∗0405 Sardinia None —

DRB1∗04 Turkey/Canary Island None —

DRB1∗04 Sweden Progressive MS —

DRB1∗04 Russia Higher T2 MRIload

—

DRB1∗0405 Japan OCB negativity —

DRB1∗04/DQB1∗0302 Finland None Weak association

DRB1∗0801 Ashkenazi Jews PP-MS —

DRB1∗12 Russia Higher T1 MRIload, higherMRI atrophy

—

DRB1∗13 Northern Italy Benign MS —

DRB1∗1303 Non-Ashkenazi Jews None —

DRB1∗17 Germany/Sweden None —

DR in general Canada None In DR15 negative families,independent contribution

DRB1∗01/07/11 — None Protective

DRB1∗01/DRw53 Finland None Protective

DRB1∗01/DQB1∗0501 Finland None Protective

DRB1∗13/DQB1∗0603 Finland None Protective

DRB1∗15021 Iran None Protective

DQA1∗0101 Colombia None —

DQA1∗0102 Colombia None —

DQA1∗0103 Colombia None Protective

DQB1∗0602 many MS populations All subtypes Independent and joint withDRB1∗1501

DPB1∗0301 Japan Classical MS —

DPB1∗0501 Japan Opticospinal(Asian) MS

—

A∗0301 Caucasians, Russia, Sweden Poor outcome,none

Partly independent of DR15

B∗07/B∗12 Caucasians, Russia Poor outcome,none

—

A∗02 Russia More benignoutcome

—

A∗0201 Sweden More benignoutcome

Protective

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cytotoxic T lymphocyte–associated antigen (CTLA)-4, the tumor necrosis factor(TNF) cluster, IL-1 receptor antagonist, IL-1, and estrogen receptor. Clinical fac-tors include earlier disease onset, more often RR-MS, female gender, optic neuritis,or spinal involvement as initial event. Immunologically, higher CSF immunoglob-ulins, oligoclonal bands (OCB), and matrix metalloproteinase 9 (MMP-9) levelshave been reported (24). DR4+ patients often have a worse clinical outcome orprogressive course than patients expressing DR15+ (Tables 1 and 2). The above-mentioned studies on HLA associations with MS are heterogeneous with respectto sample size, methodology, ethnic background, and clinical findings. In olderstudies, the exact HLA class II gene has not been determined by molecular typingtechniques. However, there is no doubt that HLA-DR and -DQ molecules are byfar the strongest genetic risk factors in MS.

Our knowledge of how certain HLA class II genes confer risk for MS or au-toimmune diseases at the molecular level is very sketchy. Several mechanismshave been considered: (a) Disease-associated HLA-DR and -DQ molecules havebinding characteristics that lead to preferential presentation of specific sets of selfpeptides, e.g., myelin peptides in MS. Currently, little data support this hypothe-sis, and comparisons of polymorphic residues in the HLA-DR and -DQ bindingpockets have not been conclusive. (b) As a variation of the first possibility, investi-gators have speculated that disease-associated HLA molecules could have bindingcharacteristics that allow only limited sets of peptides to bind, accounting forless “complete” thymic negative selection of self-reactive T cells. Diabetes-proneNOD mice and their MHC class II (I-ANOD) have been viewed as an examplefor this situation (25). Given the high frequency of most autoimmune disease–associated HLA-DR and -DQ alleles in the population and the normal cellularimmune function in the vast majority, we consider this mechanism unlikely in MS.(c) Either polymorphic residues of the T cell receptor (TCR)-exposed surfaces ofthe α-helical regions of DR/DQ-α and -β chains, such as the “shared motif” inrheumatoid arthritis–associated class II molecules (26) or TCR-contacting aminoacids of the antigenic peptide, or both, could select an autoimmune-prone T cellrepertoire. Gross abnormalities in T cell repertoires do not exist in MS patientsaccording to current data (see below). However, we recently observed that clonallyexpanded T cells from the CSF of MS patients are capable of utilizing all MS-associated HLA-DR/DQ molecules in the DR15 haplotype for recognition of largesets of peptides (M. Sospedra, unpublished observation). (d) Gene and protein ex-pression of one or several disease-associated DR and DQ alleles could be elevatedin the CNS, enhancing antigen presentation. Comparisons of the expression ofthe two MS-associated DR molecules in the DR15 haplotype, DR2a (DRA1∗0101and DRB5∗0101) and DR2b (DRA1∗0101 and DRB1∗1501), in MS patients andcontrols did not reveal general or tissue-specific upregulation of one DR allele (E.Prat, unpublished observation), but differential expression on B cells and mono-cytes. (e) Antigen presentation in the context of certain DR molecules could beshaped by proteases involved in antigen processing or by nonpolymorphic class IImolecules such as HLA-DO and -DM that are tightly linked on chromosome 6p21.3

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TABLE 2 Association of HLA-DR15 or other DR haplotypes with additional genes/chromo-somal regions (part 1), or clinical/MRI/immunological criteria (part 2)

HLA-DR geneAssociated gene orclinical/MRI/immunological factor Remark

Part 1DRB1∗1501 12p12 Gene not knownDRB1∗1501 Microsatellite close to TGFB1 Gene not knownDRB1∗1501 TGFB3 —DRB1∗1501 CTLA-4 —DRB1∗1501 Allele in TNF cluster —DRB1∗1501 Area extending to DRA1∗ promoter Gene not knownDRB1∗1501 Allele 2 of IL-1 receptor antagonist Association with

RR-MSDRB1∗1501 Association with estrogen receptor

polymorphism—

DRB1∗04/05 Association with MBP gene polymorphism inItalian and Russian MS patients

—

Part 2DRB1∗1501 Association with relapse onset MS —DRB1∗1501 Female gender, younger age at onset —DRB1∗1501 Optic neuritis first sign, spinal involvement,

early onset (all in a non-Japanese population)—

DRB1∗1501 Optic neuritis in children —DRB1∗1501 Higher CSF OCB and IgG, and MMP-9 —DRB1∗1501 Higher IL-4 and TGF-β levels, RR-MS —DRB1∗1501 Anti-MOG IgA higher in asymptomatic

relatives—

DRB1∗15-negativestatus

Worse clinical outcome —

DRB1∗04 Anti-MOG IgM elevated in patients —DRB1∗04 Worse prognosis —

and fulfill peptide-sorting and -loading functions. DM has been examined, but sofar no association has been found in MS (27). (f) Engagement of HLA class IImolecules leads to intracellular signaling events, e.g., anergy (28), which could beperturbed in patients with autoimmune diseases. There is currently no informationon this aspect in MS.

HLA class I may act independently of class II in some patients, either via similarmechanisms or by modulation of NK cell activity. The reduced number of peptide-occupied HLA class I molecules in MS patients (29), the CD8+ T cell infiltrationsin the CSF and MS plaque tissue (30, 31), and the higher expression of HLA class Iin the brain (32) suggest that the roles of HLA class I, CD8+ T cells, and NK cellsmerit further study.

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OTHER RISK-CONFERRING GENES

A recent review on the genetics of MS (14) pointedly remarked that the search forcandidate genes has been plagued by initial positive results on specific genes inone study and subsequent negative or inconclusive data in several other reports.Polymorphisms of TCR genes, immunoglobulin loci, CCR5, and CD45 are just afew examples. Without summarizing the existing literature in depth, a few chro-mosomal loci have been identified in several but not all studies, and these studiesused different methodologies, including the TCRβ chain locus, CTLA-4, TNF-αand -β alleles, and ICAM-1. CCR2, IL-10 receptor α, and Fas-L may confer pro-tective effects; CCR5, IL-10, IL-4 receptor α, IL-2 receptor β, IFN-γ , vitaminD, and estrogen receptor confer risk. With respect to CNS-related genes, Notch4,a transcription factor that is involved in both myelin development and immunefunction, neutral sphingomyelinase activating factor, ciliary neurotrophic factor,and the myelin basic protein (MBP) gene have been implicated. Other oligoden-drocyte/CNS growth factors have been studied, but no association has been found.The role of an allele of apolipoprotein E (APOE4), which is involved in lipidmetabolism and associated with the severity of Alzheimer’s disease, remains con-troversial in MS, although an association between the APOE4 allele and higherseverity/faster progression has been shown.

The above list is far from complete, and there are several reasons for the am-biguity of candidate gene searches. Methodologies and sample sizes vary; patientpopulations are often not stratified with respect to HLA, clinical, MRI-defined, orpathological phenotype; the ethnic background of subjects differs among studies;and the search often focuses on a few members of a gene family of interest, e.g., cy-tokine or TCR genes. Considering the genetic heterogeneity of the outbread humanpopulation and that almost every aspect of immune and nervous system functionoccurs and is regulated via highly complex interactions between multiple cell typesand their soluble factors, surface receptors, signaling components, growth charac-teristics, and many other molecular pathways, our limited understanding is not toosurprising.

GENOMICS STUDIES IN MS

The quantitative genetic trait has been difficult to dissect in MS and other com-plex diseases. In recent years, numerous groups have examined gene expressionrather than the presence or absence of genetic polymorphisms. The development ofmicroarray-based methods that allow the interrogation of thousands of genes in oneexperiment offers great advantages (33). Several investigators have employed mi-croarrays to study gene expression patterns in MS brain tissue or peripheral bloodsamples. Whitney et al. (34, 35) examined plaque tissue and normal-appearingwhite matter in MS patients and EAE and identified four genes consistently overex-pressed: the transcription factor jun-D, thrombin receptor protease-activated recep-tor 3, a putative ligand for IL-1 receptor-related molecule T1/ST2, and arachidonic

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acid 5-lipoxygenase, a molecule involved in leukotriene biosynthesis (35). Locket al. (36) found increased transcription of MHC class II molecules; complement;T cell and B cell genes; some cytokine genes (IL-17), as well as their recep-tors (IL-1R, TNF p75 receptor); and glial fibrillary acidic protein (GFAP) andtranscription factors. However, myelin proteins and neuronal genes were mostlyunderexpressed. EAE studies pointed at the relevance of G-CSF and FcRγ (36).Further studies found differential abundance of CD4, MAPKK1, nerve growth fac-tors, HLA-DRα, and proinflammatory cytokines including osteopontin, but alsosome Th2 genes, α-B crystallin, and others (37–40). These studies have not beenformally compared; however, immune system–related genes are prominently ex-pressed, particularly at the acute stage of MS, and there are quantitative rather thanqualitative differences between early and later stages of the disease. Examinationof normal-appearing white matter, i.e., areas of the brain that appear macroscop-ically normal but are microscopically abnormal, demonstrated upregulation ofgenes involved in homeostasis and neural protection (41).

Expression studies in peripheral blood mononuclear cells (PBMC) have yieldedsimilarly large numbers (42) of differentially expressed genes, and many are re-lated to immune function, including MHC class II molecules; cytokines (TNF-α,IFN-γ , LTB, TNF-α receptor-associated factor 5); adhesion molecules (CD11a,CD18, CD49, integrin β7); costimulatory molecules (SLAM); T cell transcripts(TCRα, MAL); B cell or NK cell transcripts; signaling molecules (ZAP70); pro-teases involved in antigen processing; and many others with unknown relation toMS (42). The differential expression of only two genes from chromosome 6p21.3,i.e., heat shock protein 70 and histone family member 2, allowed investigators toseparate patients and controls with 80% accuracy (43), and with the entire set ofdifferentially expressed genes, one can accurately distinguish the two groups (43;G. Blevins, unpublished observation). Dissection of the mechanism of action ofMS therapies by gene expression profiling has shown that IFN-β has not only im-munomodulatory effects (e.g., increase of IL-10) but also proinflammatory effects(e.g., upregulation of CCR5 and the IL-12 receptor β2 chain) (44). Gene expres-sion profiling also identified genes associated with partial responsiveness (e.g.,IL-8 or TRAIL) to IFN-β therapy (45, 46). Although widely perceived as “fishingexpeditions” and not hypothesis-driven experiments, gene expression profiling islikely to complement genetic studies and also to be instrumental in other aspectsof MS research, such as identifying important functional pathways and treatmentmechanisms.

ETIOLOGY OF MS: NONGENETIC FACTORS ANDINFECTIOUS TRIGGERS

Nongenetic Factors in the Etiology of MS

The relatively low concordance rate of identical twins indicates a contribution ofnongenetic factors to MS etiology (14, 47). This argument has to be considered

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with some caution because studies in congenic mice with gradually increasingnumbers of lupus-associated genes have shown that the rate of disease expressioncan be “titrated,” i.e., the fraction of animals that developed lupus was determinedby the number of disease-linked genes under identical environmental influences(48). Among putative environmental factors, both infectious agents and behav-ioral or lifestyle influences have been proposed to induce or contribute to diseaseexpression (49). The fact that women with the disease outnumber men with MSby 1.6–2.0:1 suggests hormonal variables as risk factors. This is supported by(a) lower relapse rates during, and disease rebound after, pregnancy (50); (b) theworsening of MS during menstruation; (c) the correlation of high estradiol and lowprogesterone with increased MRI disease activity; (d) gender differences in EAEsusceptibility related to the protective effect of testosterone; and finally (e) thetherapeutic effects of estriol in RR-MS (51). The precise mechanisms by whichsex hormones may influence MS susceptibility are not known, but the stimula-tory effects of estrogens on proinflammatory cytokine secretion and the reverse byandrogens probably represent one mechanism.

Environmental contributions to the etiology for MS are supported by a numberof factors. (a) The north to south gradient in disease prevalence on the north-ern hemisphere and the opposite on the southern. (b) MS distribution cannot beexplained by population genetics alone. Although regions to which Northern Eu-ropean descendents migrated show high prevalence rates, these rates among Cau-casians outside Europe are only half those in many parts of Northern Europe.(c) Migration studies show that if one migrated from an area of high incidenceof MS to an area of low incidence before age 15–16, the low risk was acquired,whereas migration after 15–16 did not change the risk (52). One proposed causativefactor is the decrease in sunlight exposure depending on the latitude. UV radia-tion may exert its effects either by influencing immunoregulatory cells or by thebiosynthesis of vitamin D (53). The latter notion is supported by EAE data and theassociation of a vitamin D receptor polymorphism with MS in Japan. Melatoninsecretion also depends on sunlight exposure. The lack of sunlight could induce anexcess of melatonin, which enhances Th1 responses.

The geographical distribution also reflects the economic level of the country.The incidence of MS in Asia is overall low, with the highest prevalence in Japan, themost developed country in the area. Furthermore, prevalence rates have increasedwith the socioeconomic development in previous decades, which has been relatedto industrialization, urban living, pollution, occupational exposures to solvents,changes in diet and breastfeeding, smoking habits, and reduced UV light expo-sure. Finally, the delayed exposure to or overall reduction in childhood infectionsin developed countries is another factor and has led to the “hygiene hypothesis.”According to this hypothesis, which is supported by findings in type 1 diabetes andEAE, there is a skewed immune responsiveness and increased propensity to de-velop autoimmune reactions/diseases (Th1-mediated) and allergy (Th2-mediated)in populations with delayed exposure to or overall reduction in childhood infec-tions. However, this hypothesis is difficult to prove.

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INFECTIOUS AGENTS AS TRIGGERS OF MS

Viral and bacterial infections are logical candidates as environmental triggers ofMS. However, what has been stated for genetic studies also applies to researchon infectious agents. Numerous reports have claimed to identify MS triggers, andalmost universally these observations have later not withstood scrutiny (54, 55).Prospective studies have shown that MS relapses often follow viral infections (56).The temporal patterns and the occurrence of “MS epidemics,” i.e., sudden increasesin MS incidence in small, previously isolated communities, such as the one onthe Faroe Islands, also point toward an infectious agent (52), although these arenot uncontested. Further evidence for viral or bacterial triggers stems from EAEstudies. Almost 100% of transgenic mice expressing a TCR that is specific foran encephalitogenic peptide of MBP develop EAE when the transgenic mice arehoused under nonpathogen-free conditions, whereas the same animals housed ina specific-pathogen-free facility remained disease free (57).

The viral etiology of a number of human demyelinating diseases [progres-sive multifocal leukoencephalopathy caused by papovavirus JC; postinfectious en-cephalitis and subacute sclerosing panencephalitis (SSPE), both caused by measlesvirus; herpes simplex virus (HSV); HIV encephalopathy] explains the continuedinterest in viruses as triggers for MS (54, 55). Animal models of virus-induceddemyelinating diseases, such as encephalitis or encephalomyelitis by Theiler’smurine encephalomyelitis virus (TMEV), canine distemper virus, neurotropicstrains of mouse hepatitis virus, Semliki Forest virus, Visna virus, and rat-adaptedmeasles virus (54, 55), also support the possible involvement of a virus in MS.

Among viruses that are pathogenic in humans, those that induce persistent in-fection, such as herpes- or retroviruses, are suitable candidates and have beenstudied widely in MS. Herpesviruses are of particular interest owing to their neu-rotropism, ubiquitous nature, and tendency to produce latent, recurrent infections.Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) are the leading can-didates. The seroprevalence for both is high, i.e., >80% for HHV-6, a lymphotropicand neurotropic β-herpes virus, and 90% for EBV, a lymphotropic γ -herpes virus.HHV-6 can lead to meningoencephalitis, and several additional observations sug-gest a role in MS, including its detection in oligodendrocytes in MS plaque tissue(58) (but also in normal brains), the infection of astrocytes, and the presence ofHHV-6 DNA and anti-HHV-6 IgG and IgM antibodies in serum and CSF of MSpatients. However, the DNA and serological data are controversial (reviewed in59). The existence of two different HHV-6 variants may account for some of thediscrepancies. The role of HHV-6 variant A in MS is supported by its higherneurotropism, increased lymphoproliferative responses against variant A in MSpatients (60), and its DNA presence in CSF from MS patients.

EBV has also been linked with MS. Anti-EBV antibodies are elevated in patientswith MS, i.e., the seropositivity rate of MS patients is 100% versus approximately90% in the general population, and MS patients reactivate latent EBV infectionsmore often, correlating with relapses (61). Serum anti-EBV IgG levels prior to

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onset of MS have been reported as a strong disease predictor, a history of infectiousmononucleosis is more common in MS patients, and the risk of developing MSis higher for individuals who suffered from infectious mononucleosis at a youngage (62). Furthermore, some patients with neurological sequelae of primary EBVinfection develop MS.

Human herpes virus 1 (HSV-1) and varicella zoster virus (VZV or HSV-3)have also been considered as MS-triggering agents on the basis either of CSFantibody studies, casuistic observations, or the finding that VZV encephalitis ischaracterized by demyelination. Finally, MS-associated retroviruses have beenlinked with disease on the basis of the detection of extracellular virions in plasmaand CSF of MS patients; however, their role is currently not clear.

Among bacteria, Chlamydia pneumoniae (Cpn) has been implicated in MS. Cpnis a Gram-negative intracellular bacterium and common pathogen of the respiratorysystem. Following an initial report (63), many studies examined an associationbetween Cpn and MS. Current data are contradictory. Whereas one study reportedthe presence of Cpn in the CSF of a large percentage of MS patients comparedwith controls (64), other studies failed to observe an association between Cpn andMS (65).

The difficulty in identifying a single microorganism as the cause of MS proba-bly indicates that Koch’s paradigm “one organism, one disease” does not apply tothis complex disease. Current data suggest that MS could be induced and/or exac-erbated by many different microbial infections, and the responsible agents are mostlikely ubiquitous pathogens that are highly prevalent in the general population.

MECHANISMS: HOW INFECTIOUS AGENTS MAYINDUCE MS

Two main mechanisms have been proposed to explain how infections could in-duce MS: (a) molecular mimicry, i.e., the activation of autoreactive cells by cross-reactivity between self-antigens and foreign agents; and (b) bystander activation,which assumes that autoreactive cells are activated because of nonspecific inflam-matory events that occur during infections. A third proposal is that infectionsinduce MS through a combination of these two mechanisms.

Molecular Mimicry

Molecular mimicry involves reactivity of T and B cells with either peptides orantigenic determinants shared by infectious and self-antigens. The recognition ofself-antigens at intermediate levels of affinity by T cells during thymic selectionleads to positive selection and export of these T cells to the periphery. Cross-reactivity of these potentially self-reactive T cells with foreign antigens can leadto activation during infection, migration across the blood-brain barrier (BBB), CNSinfiltration, and, if they recognize antigens expressed in the brain, tissue damageand potentially an autoimmune disease like MS (Figure 2).

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Figure 2 The evolution of the molecular mimicry concept and activation ofautoreactive T cells via cross-reactivity with foreign antigens (for details, seetext).

For example, MBP is a candidate autoantigen in MS on the basis of numerouspieces of evidence (6). MBP-specific T cells can be isolated from MS patientsand controls (66–72). However, their activation state in MS patients, proinflam-matory phenotype, higher antigen avidity, and preferential memory origin suggestthat they had been activated in vivo, e.g., by cross-reactive infectious antigensduring infections. Many studies have looked for cross-reactive antigens betweenMBP and foreign agents. Initially, the search was guided by the concept that

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humoral and cellular immune reactivity is exquisitely specific and that completehomology between foreign proteins and MBP is required for molecular mimicry.Although examples of such stringent homology have been reported for MBP andviruses (73, 74) (Figure 2), complete sequence matching is a rare event. Subse-quent research of the molecular requirements for T cell recognition found thatcertain amino acid positions in a peptide are more critical than others for theinteractions within the trimolecular complex, and most residues, except for theprimary TCR contact, allowed for some degree of variation (75). On the basis ofthese observations, a search algorithm assumed that molecular mimicry can oc-cur as long as a MHC and TCR contact motif is preserved (76) (Figure 2). Theactivation of MBP-specific T cell clones (TCC) derived from MS patients by vi-ral and bacterial peptides sharing this motif with MBP confirmed the predictionthat sequence homology was not required for cross-recognition (76) (Figure 2).Subsequently, the recognition by a MBP(83−99)-specific TCC was systematicallydissected using single amino acid substitutions in each position of the peptidesequence (77). These data demonstrate that cross-reactivity can occur with pep-tides that share no amino acid in their sequence and that each amino acid in thepeptide contributes independently to TCR recognition (78) (Figure 2). Recently,the concept evolved even further; Lang et al. (79) showed that different peptidesbound to different class II molecules can lead to cross-reactivity by the same TCRas long as the complexes share similarity in charge distribution and overall shape(Figure 2). Together, these observations offer new perspectives on the conceptof molecular mimicry and indicate that cross-reactivity occurs frequently. Addi-tional evidence for molecular mimicry stems from animal experiments showingthat mice expressing viral proteins as tissue-specific transgenes develop autoim-mune diseases after viral infection (80, 81). Recently, a model for virus infectionthat leads to molecular mimicry has been developed, in which an encephalito-genic virus (TEMV) encodes a mimic peptide for an encephalitogenic myelinproteolipid protein (PLP) that is naturally expressed by Haemophilus influenzae.The infection with this recombinant virus induces early onset of disease, whichindicates that CNS infection with a pathogen containing a mimic epitope for aself-myelin antigen can induce a cross-reactive T cell response, resulting in au-toimmune demyelinating disease (82). Although all these findings demonstrate thatmolecular mimicry is a viable hypothesis that can explain the link between infec-tion and MS, evidence for this phenomenon in human autoimmune diseases is stillscarce.

Bystander Activation

Bystander activation mechanisms can be classified into two categories. The firstcategory encompasses TCR-independent bystander activation of autoreactive Tcells by inflammatory cytokines, superantigens, and molecular pattern recog-nition, e.g., Toll-like receptor (TLR) activation. The second category involvesthe unveiling of host antigens and the adjuvant effect of infectious agents on

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antigen-presenting cells (APCs). Several proinflammatory cytokines and chemo-kines are produced during infection, and these molecules have long been con-sidered the main activators of virus-specific CD8+ T cells and inducers of theautoimmune process (83). Most of the activated CD8+ T cells are specific for viralantigens, however, and cytokines alone are unlikely to cause the activation and dif-ferentiation of T cells in the absence of specific antigen (84), which suggests thatbystander activation requires the cooperation of several mechanisms to induce au-toimmunity. Although the administration of cytokines can induce disease relapsesin EAE, there are few examples in which the local overexpression of inflammatorycytokines/chemokines alone can break tolerance in healthy animals. The local ex-pression of IL-2, IL-12, and IFN-γ -inducible protein (IP)-10 in diabetes can leadto inflammation but not to clinical disease, and only the overexpression of IFN-γ inpancreatic β cells disrupts tolerance to autoantigens, probably owing to enhancedpresentation of self-antigens.

Superantigen exposure has also been proposed as a bystander activation mech-anism. These toxins can induce relapses in the EAE model via interactions withMBP-specific TCC that express certain TCR Vβ chains (85).

Bystander activation via another group of infectious agent–derived and proin-flammatory factors, such as TLRs, has also been described (86). One of them,lipopolysaccharide (LPS), binds to TLR4 and initiates innate immune responsesto common Gram-negative bacteria such as Cpn. TLR4 activation by LPS increasesthe expression of cytokines as well as of reactive oxygen species. TLR4 in the CNSis mainly expressed on microglia but not on astrocytes or oligodendrocytes. LPS-TLR4 interactions may occur in MS during an infection with bacteria such asCpn and induce the activation of monocytes and microglia, i.e., the adjuvant effecton APCs. Alternatively, LPS-TLR4 interactions may activate autoreactive T cellsin the periphery. Bacteria injected into the brain parenchyma are able to induceinflammatory responses only after peripheral sensitization.

Another mechanism of bystander activation that depends on specific TCR recog-nition is the unveiling of host antigens as a consequence of viral tissue damage.Activated virus-specific T cells traffic to the infected tissue, where they recognizeviral epitopes and kill infected cells, resulting in the destruction of self-tissue andthe release of autoantigens. The presentation of autoantigens together with theadjuvant effect of infectious agents can then result in the de novo activation of au-toreactive T cells and later to epitope spreading. This process occurs in the TMEVmouse model for MS, in which an initial virus-specific T cell response broadens orspreads to myelin proteins during persistent infection of the CNS (87). Spreading ofthe T cell response can include the presentation of cryptic epitopes that are usuallynot processed or presented as immunodominant epitopes but that can be presentedduring specific conditions associated with viral infection (88). During viral in-fection, the expression of self-proteins in the infected tissue is often upregulated(89), tissue-specific APCs are activated, and the expression pattern of proteases inthese APCs can be altered, which leads to processing of cryptic epitopes that arenot generated during “normal” processing (90). The recognition of such cryptic

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epitopes is probably more important during progression and perpetuation of theautoimmune response.

Recently, Pender (91) suggested that MS, like other chronic autoimmune dis-eases, could be based on infection of autoreactive B lymphocytes by EBV. In thisscenario, autoreactive B cells are infected by EBV, proliferate, and turn into latentlyinfected B cells that are resistant to apoptosis because they express virus-encodedantiapoptotic molecules. The presence of infected B cells in the target tissue canresult in costimulation of autoreactive T cells, which prevents these cells fromundergoing activation-induced apoptosis.

THE “MAJOR PLAYERS”

CD4+ T Cells

EVIDENCE FOR INVOLVEMENT OF CD4+ T CELLS IN MS Following the descriptionof MS by Charcot in 1868 (92), and the observation by Pasteur at the turn to thetwentieth century (93) of acute postvaccinal encephalomyelitis in rabies vaccinees,Rivers showed in 1933 (94) that the injection of spinal cord or brain homogenatesinto healthy primates caused a disease similar to MS, leading to the hypothe-sis that MS is an autoimmune disease. Several decades later, investigators beganto study systematically the experimental disease in rodents and made the semi-nal observations that still dominate our thinking about the pathogenesis of MS(8, 9, 95). They showed that the injection of defined protein components of themyelin sheath together with an adjuvant into naive susceptible animals causedeither an acute, chronic, or relapsing-remitting encephalomyelitis, which is nowreferred to as EAE. The observation that EAE could be transferred by in vitroreactivated myelin-specific CD4+ T cells (passive or adoptive transfer EAE) (8,9) convincingly documented that EAE can be directly induced with autoreactiveT cells in naive animals. Unlike myasthenia gravis, which is also an autoimmunedisease affecting striated muscle, EAE cannot be transferred by antibodies. Thisfact led investigators to conclude that MS is likely a T cell–mediated autoim-mune disease. As we discuss below, this view is too simplistic. However, currentevidence on the induction and perpetuation of MS still favors CD4+ autoreac-tive T cells as a central factor for the autoimmune pathogenesis of MS by thefollowing arguments: (a) CD4+ T cells contribute to the CNS- and CSF-infiltratinginflammatory cells in MS; (b) genetic risk is to a substantial degree conferred byHLA-DR and -DQ molecules; (c) humanized transgenic mice expressing eitherHLA-DR or -DQ molecules are susceptible to EAE (96–98), and miceexpressing both MS-associated HLA-DR molecules and MS patient–derived MBP-specific TCR develop spontaneous or induced EAE (99, 100); (d) a therapeutic trialwith an altered peptide ligand (APL) of MBP(83−99) induced cross-reactive CD4+

T cells with Th1 phenotype that led to disease exacerbations of MS patients (101);(e) antibody production, CD8+ maturation, and many other steps of adaptive and

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innate immune function are at least in part controlled by CD4+ helper T cells.Unlike our previous review of this subject (6), we do not describe EAE data indetail here, but rather refer the reader to the original literature and reviews (8, 102,103). We focus instead on MS.

One of the first striking observations in the early investigations of the involve-ment of CD4+ T cells in MS was that MBP-specific T cells were readily found inboth MS patients and healthy controls (66), indicating that previous concepts aboutthe efficiency of central tolerance mechanisms and the elimination of autoreactiveT cells were probably not correct (68–71). The fact that such autoreactive T cellsfrom the normal T cell repertoire of Lewis rats can induce EAE (104) suggestedto investigators that their equivalent in humans might also be relevant for MS.During the subsequent two decades, every aspect of CD4+ T cells in MS has beenthe subject of exhaustive research. We are not able to cover all these data in detail,but we summarize the main findings.

FREQUENCY OF CD4+ AUTOREACTIVE T CELLS Frequencies of autoreactive T cellsin MS patients and healthy controls vary greatly depending on the methodology(71, 72, 105–109). Whereas tissue culture–based techniques have shown frequen-cies of about 1 MBP-specific cell per 106−107 PBMC (71, 105), approximately1–2 orders of magnitude higher numbers were observed with enzyme-linked im-munospot (ELISPOT) assays, which detect IFN-γ -secreting cells (72). Newermethods, which employ quantitative polymerase chain reaction to follow individ-ual TCC via their specific TCR CDR3 regions, observe frequencies of 1/104 oreven higher (107, 109). Flow cytometry–based techniques that follow the prolifer-ating cell fraction upon stimulation with a myelin antigen observe frequencies in asimilar range (110). Tetramer-based assays currently do not work for autoreactiveHLA class II–restricted T cells, probably owing to low-affinity TCR recognitionof autoantigens. Most studies comparing MBP- or PLP-specific T cells in MSpatients and controls observe elevations in precursor frequencies in MS patients(111). Furthermore, the number of myelin-specific T cells with mutations of thehypoxanthine phosphoribosyl transferase gene, which occur in the proliferatingT cell pool, is elevated in MS (112, 113). Up to 2000-fold expansions of MBP(83−99)-specific T cells have been described during exacerbation of patients in a treatmenttrial with an APL based on the immunodominant MBP(83−99) peptide (101). MostAPL-specific T cells cross-reacted with MBP(83−99), and these cells were alsofound in the CSF and exhibited a Th1 phenotype, all supporting their involvementin disease exacerbation (101). Finally, TCR CDR3-based molecular tracking ofindividual clones showed that MBP- and APL-specific T cells had preexisted inthe patient’s peripheral blood long before APL therapy but were markedly ex-panded during disease exacerbation (107). Most studies of autoreactive T cellsin MS used relatively high concentrations (10–50 µg/ml) of either whole nativeor recombinant proteins or peptides. Under normal conditions, and even underdisease conditions such as stroke, such high concentrations of myelin antigens areprobably rarely reached, and T cell activation by autoantigens will only result if

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other factors, such as strong activation of innate immune mechanisms, upregula-tion of MHC and costimulatory molecules, and proinflammatory cytokines, occur.However, high-avidity T cells that respond at low antigen concentrations to myelinproteins/peptides and that are likely more relevant to disease are clearly also in-creased in MS patients and mostly express a proinflammatory phenotype (108).

Antigen Specificity of Myelin-Specific CD4+ T Cells

MYELIN BASIC PROTEIN (MBP) MBP is the best-studied myelin protein in MS. Itis the second most abundant myelin protein (approximately 30%–40%) after PLP,is relatively easy to isolate owing to its physicochemical characteristics, and wasthe first that was used extensively in EAE. There are five MBP isoforms with14.0–21.5 kDa molecular weights in mammals that result from differential splic-ing of eleven axons within the Golli-MBP locus (114). The highly basic MBP ispositioned at the intracellular surface of myelin membranes, and via interactionswith acidic lipid moieties it is involved in maintaining the structure of compactmyelin. The most abundant 18.5 kDa isoform (170 amino acid length) has beenused in most immunological studies. Unlike MOG and PLP, MBP is found in sig-nificant quantities in both central and peripheral myelin, and MBP transcripts havealso been demonstrated in peripheral lymphoid organs (115). EAE can be inducedwith MBP in several mouse and rat strains, guinea pigs, and nonhuman primates(103). The most important encephalitogenic areas are depicted in Figure 3. Animportant parallel between rodent and primate EAE models and MBP-specificimmune responses in humans is the striking overlap between epitopes that are en-cephalitogenic in the context of EAE-associated MHC class II alleles and MBP re-gions that are immunodominant in the context of MS-associated HLA-DR alleles,i.e., HLA-DR2a (DRB5∗0101), -DRb (DRB1∗1501), and -DRB1∗0401/0404/0405(69–71, 116, 117) (Figure 3). This applies to the immunodominant MBP(83−99) orMBP(84−102) epitope, a promiscuous binder to all the above MS-associated HLA-DR molecules (118–120), as well as to the immunodominant MBP(111−129) epitopein the context of DRB1∗0401 (121) and the region of MBP that is immunodominantwith DR2a (71, 122) and other DR alleles (123). For high-avidity myelin-specificT cells, MBP(83−99) is not immunodominant, but MBP(13−32), MBP(111−129), andMBP(146−170) are (108). Most of these peptides are promiscuous HLA-DR binders;however, the predicted affinity to HLA-DR2a, -DR2b, -DR4, and other DR allelesis low, indicating that deletion of T cells with high functional avidity for theseMBP epitopes in the thymus is incomplete. This situation is similar to MBP Ac1-11 epitope in PL/J mice (114, 124). The poor binding affinity of the latter MBPepitope to IAu supports the view that complexes of MBP Ac1-11 with IAu are un-stable and therefore inefficient in negative selection (125). MBP Ac1-11-specificTCR transgenic mice develop EAE depending on the level of microbial exposureor after induction with pertussis (57, 126). The encephalitogenic potential of aMS patient–derived T cell was demonstrated in a transgenic mouse expressing aMBP(84−104)-specific TCR and HLA-DR15 (99). EAE could readily be induced,

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Figure 3 Immunodominant regions of MBP in humans and various EAE models indifferent species. MHC class II–restricted epitopes are shown on top (green), thosethat are recognized in the context of MHC class I and/or encephalitogenic in EAE atthe bottom (blue).

and about 4% of these animals developed spontaneous disease. Furthermore, thesame TCR cross-reacts with an EBV-derived peptide in the context of DR2a, sup-porting molecular mimicry (79). The complex of HLA-DR2b and MBP(84−102) wasalso detected in the brains of MS patients via staining with a monoclonal antibody,which supports the notion that the immunodominant autoantigenic peptide is pre-sented locally (127). A recent humanized transgenic mouse model that combinesanother MS patient–derived MBP(83−99)-specific TCR and DR2a also readily de-velops active and passive EAE, although we do not know yet whether spontaneous

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disease will occur (J. Shukaliak-Quandt, unpublished observation). MBP(83−99)

has received the most attention; however, EAE can also be induced in humanizedtransgenic mice expressing a MBP(111−129)-specific MS patient–derived TCR to-gether with the restriction element DRB1∗0401 (100). Interestingly, only adoptivetransfer EAE was inducible in this model, and some animals not only develop signsof conventional EAE, i.e., limp tail, flaccid hind limb paresis, or paralysis, but alsoshow signs of involvement of caudal cranial nerves with swallowing difficultiesand ataxia, which indicate that clinical/phenotypic heterogeneity is related to theinducing myelin peptide (102).

Additional evidence supporting a role for MBP in MS include cross-reactivitybetween MBP(84−102)-specific Th1 cells and an identical sequence in the U24antigen of HHV-6 (74), broader responses to MBP, and intra- and interindividualfluctuations of the specificities over time, without clear relation to inflammatoryMRI activity.

PROTEOLIPID PROTEIN (PLP) PLP is the most abundant CNS myelin protein (about50%), highly hydrophobic and evolutionarily conserved across species. In mice,there are two main transcripts, the full-length 276 amino acid isoform; and DM-20, an isoform that lacks 35 amino acids and is mainly expressed in brain andspinal cord prior to myelination but also in peripheral lymphoid organs, wherefull-length PLP is barely found (114, 115, 128). The differential peripheral expres-sion is relevant for one major encephalitogenic and immunodominant PLP(139−154)

peptide that is contained in full-length PLP, but is not contained in DM-20 (115,128) and therefore is not available for thymic negative selection. Consequently,high frequencies of PLP(139−154)-specific T cells have been observed even innaive unprimed animals (128, 129). PLP is a stronger encephalitogen comparedwith MBP, at least in some EAE models, particularly in SJL/J mice, in whichPLP(139−151) is dominant (130, 131). PLP TCR transgenic mice on the SJL/Jbackground develop spontaneous EAE with very high frequency (129). UponEAE induction with whole spinal cord homogenate in SJL/J mice, the dominantT cell response is directed against PLP(139−151), and during disease relapses pre-dictable epitope spreading occurs to PLP(178−191) and later to MBP(89−101) (130,131). If EAE in SJL/J mice is induced with either the secondary PLP(178−191) epi-tope or with MBP(89−101), further waves of the disease always involve reactivityto PLP(139−151) (130, 131). Numerous other PLP peptides are encephalitogenic,including PLP(178−191), PLP(43−64), PLP(56−70), and PLP(104−117) in SJL/J mice,PLP(217−233) in Lewis rats, and PLP(56−70) in Biozzi mice. Although examined lessextensively for PLP, the above parallels between encephalitogenic MBP epitopesin EAE and immunodominant peptides in humans are also observed. PLP(104−117),PLP(142−153), PLP(184−199), and PLP(190−209) peptides are immunodominant in thecontext of the MS-associated DR2 alleles, but these peptides also bind to otherHLA-DR alleles (132, 133). Further immunodominant epitopes are PLP(30−49),PLP(40−60), PLP(89−106), and PLP(95−116) (97, 134−136). As is the case in themouse, the human thymus does not express PLP(139−151), which at least in part

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explains the immunodominance in humans. The frequencies and skew toward aTh1 phenotype of PLP-specific T cells are increased in MS, but not in every study.PLP(139−151) and PLP(178−191) are main targets of high-avidity T cells and are clearlyelevated in MS patients (108).

MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG) MOG, a 218 amino acidtransmembrane glycoprotein of the Ig superfamily, is much less abundant thanthe major myelin proteins (0.01%–0.05%), and it is not located in compact myelinbut rather on the outer surface of the oligodendrocyte membrane. Owing to this“strategic” location, it is directly accessible to antibodies and believed to be rel-evant as a target for both cellular and humoral immune responses in MS. MOGis expressed late in myelination and is only found in the brain/spinal cord andthe retina, not in peripheral nerve. Furthermore, MOG expression is either com-pletely or almost completely lacking in peripheral lymphoid tissues (114, 115).MOG-induced EAE is best examined in C57/BL6 mice, in which the MOG(35−55)

peptide induces a chronic, nonrelapsing EAE (137). A recent MOG TCR transgenicmouse model on the B6 background showed spontaneous EAE with inflammation,demyelination, and axonal damage in brain and spinal cord in a small fraction ofanimals, while 35% developed spontaneous optic neuritis (138). Optic neuritis isalso seen in MOG-induced EAE in DA rats (102), and the relatively higher ex-pression of MOG in the optic nerve has been proposed as one explanation for theinvolvement of the optic nerve (138). Differences in lesion location, as well as inthe involvement of antibodies versus T cells in different EAE models support thenotion that the inducing antigens and immunogenetic background contribute todisease phenotype (102, 139).

Overall, much less information is available on the fine specificity of humanMOG-reactive T cells when compared with MBP and PLP. Immunodominantepitopes have been located in the Ig-like extracellular domain of MOG(1−22),MOG(11−30), MOG(21−40), MOG(31−50), MOG(34−56), MOG(63−87), MOG(64−96),MOG(71−90) (140−142), which also harbor several encephalitogenic epitopes (143),but immunodominant areas have also been found in the intracellular parts ofMOG. MOG(146−154) is immunodominant with both DR15 (DRB1∗1501) and DR4(DRB1∗0401) (144). Weissert et al. (144) reported stronger responses toward intra-cellular portions of MOG and to different MOG peptides in MS patients, whereasthe reverse was observed by Lindert et al. (145). MOG(1−20) and MOG(35−55) pep-tides are among the 6/15 myelin peptides from MBP, PLP, MOG, and CNPase thataccount for clearly elevated high-avidity myelin-specific T cell responses in MSpatients, which supports the importance of MOG (108).

Other Myelin and Nonmyelin Antigens asTargets for CD4+ T Cells

Investigators have examined the role of a few other myelin components andnonmyelin proteins and glycolipids as antigens for CD4+ T cells. The order in

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which they are mentioned here does not reflect their importance, which is not yetknown.

MYELIN-ASSOCIATED GLYCOPROTEIN (MAG) MAG is a large (approximately100 kDa) myelin glycoprotein located at the inner surface of the myelin sheathopposing the axon surface. It accounts for less than 1% of total myelin proteinin the CNS and is even less abundant in the peripheral nervous system (PNS).The pathogenetic relevance of MAG has been documented for polyneuropathiesby anti-MAG IgM (146). MAG(97−112) is encephalitogenic in ABH (H-2Ag7) mice(147), and elevated MAG-specific T and B cell responses have been observed inthe CSF of MS patients by ELISPOT assays (148). Among the few MAG peptidesthat have been examined, C-terminal areas, i.e., MAG(596−612) and MAG(609−626),are relatively immunodominant (148). The preferential location of CNS lesions incerebellum, centrum semiovale, and forebrain in MAG-induced EAE in Lewis ratssupports the notion that the antigen specificity is related to lesion location (102).

2′,3′-CYCLIC NUCLEOTIDE 3′ PHOSPHODIESTERASE (CNPase) CNPase exists in twosplice variants (CNPase I and II, 46 kDa and 48 kDa) and makes up 3%–4% oftotal myelin protein. It is located in oligodendrocytes, mainly around the nucleusand in the paranodal loops, but it is also expressed in peripheral Schwann cells and,although much less, in lymphoid tissues. Its exact role is not clear. Encephalito-genicity could not be demonstrated so far (147); however, immunization of Lewisrats with a CNPase peptide with homology with mycobacterial HSP65 resultedin protection from EAE (149). CNPase is immunogenic both in rodents and inhumans, and studies of the reactivity to either recombinant or native CNPase andto overlapping CNPase peptides have located a number of areas with promiscuousbinding to several HLA-DR alleles, including the MS-associated DR15 molecules(150, 151). A C-terminal area [CNPase(343−373)] is one of the immunodominantepitopes that is recognized preferentially by high-avidity myelin-specific T cellsof MS patients (108).

MYELIN-ASSOCIATED OLIGODENDROCYTIC BASIC PROTEIN (MOBP) MOBP was di-scovered recently. Several splice variants exist, and the 81 amino acid isoform ismost abundant in rodent and human myelin. MOBP is exclusively expressed inoligodendrocytes, appears late in myelination, and is located in the major denseline of compact myelin. MOBP is encephalitogenic in SJL/J mice, and the en-cephalitogenic epitope is located within amino acid 37–60 (152, 153). Preliminarystudies of cellular anti-MOBP responses in MS patients and controls identified oneimmunodominant region, MOBP(21−39) (152), and the reactivity of MOBP-specificT cells cofluctuated with inflammatory MRI activity (154).

OLIGODENDROCYTE-SPECIFIC GLYCOPROTEIN (OSP) OSP is the third most abun-dant myelin protein (7%), is expressed in the CNS and testis, and is located intight junctions. These characteristics led it to be grouped in the family of tight

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junction proteins and to be renamed as OSP/Claudin-11. Several OSP peptidesinduce EAE in SJL/J mice, and OSP-specific antibodies are found in the CSF ofRR-MS patients (155). By testing PBMC from RR-MS and SP-MS patients withoverlapping OSP peptides, investigators identified a number of immunogenic ar-eas and observed overall strong responses in both healthy controls and RR-MSpatients but decreased reactivity in SP-MS (156).

α-B CRYSTALLIN (αB-C) Unlike the myelin proteins discussed above, αB-C wasidentified as a candidate target in MS patients and not in EAE models. Van Noortand colleagues (157) fractionated MS brain–derived proteins and then tested theproliferation of PBMC from MS patients and healthy controls against brain proteinfractions. They observed prominent reactivity in one of the fractions and identi-fied the small heat shock protein αB-C as the relevant antigen (157). αB-C is amajor constituent of the eye lens, but it is also expressed in astrocytes and oligo-dendrocytes in active MS lesions. A cryptic epitope of α-B crystallin, αB-C(1−16),is weakly encephalitogenic in Biozzi ABH mice. In addition to the demonstra-tion of strong responses to αB-C-containing MS brain–derived protein fractions,DRB1∗1501-restricted CD4+ Th1 T cells in MS patients responded to peptidesαB-C(21−40) and αB-C(41−60), although less to αB-C(131−150) (158). Other inves-tigators documented comparable T cell responses to αB-C in MS patients andhealthy controls (159).

S100β PROTEIN Linington and colleagues (160) examined the astrocyte-derivedcalcium-binding protein S100 in Lewis rats and observed a strong immune responseagainst the S100β epitope (amino acid 76–91). Unlike myelin antigens, S100 im-munization or adoptive transfer of S100-specific T cells led to a panencephalitisand uveoretinitis. However, disease induction with S100 led to little if any clinicaldeficit (160). The lack of clinical disease was related to the decreased macrophagerecruitment, despite massive T cell infiltrates (160). Also, unlike MBP-specificT cell lines, S100-specific T cells did not show cytotoxic activity. These observa-tions parallel data from MS patients. Both CD4+ and CD8+ T cells specific forS100β can be isolated with no differences among the groups (159, 161). S100-specific CD4+ T cells exhibited cytotoxic activity less often compared with MBP-specific T cells from the same donors (161).

TRANSALDOLASE-H (Tal-H) Tal-H was discovered on the basis of homologies withthe gag p17 protein of human T lymphotropic virus type I (162). Tal-H is a keyenzyme of the pentose phosphate pathway and is expressed in oligodendrocytes,Schwann cells, and lymphoid tissues. High-affinity antibodies against Tal-H havebeen found in the serum and CSF of MS patients, and Tal-H also stimulates pro-liferation of MS PBMC (163).

IMMUNOGLOBULINS AS T CELL ANTIGENS Vartdal and colleagues (164) examinedthe interesting hypothesis that the intrathecal Ig synthesis is involved in

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perpetuating the CD4+ T cell response. They found proliferative reactivity ofT cells to CSF Ig in 14 out of 21 MS patients and 4 out of 17 other neurologicalcontrols, and preliminary studies indicate that CD4+ T cells responded in a DR-restricted fashion (164). We have recently identified an IgG peptide as one targetof a CD4+ TCC (MN36) that was clonally expanded in the CSF of a MS patientduring exacerbation (M. Sospedra, unpublished observation). The specificity ofthe TCC was identified with an unbiased technique, i.e., positional scanning com-binatorial peptide libraries, and it supports the above hypothesis (164, 165) thatCSF-derived Ig may serve as an autoantigen that perpetuates the autoreactive Tcell response.

LIPID COMPONENTS AS ANTIGENS FOR CD4+ T CELLS IN MS Paralleling the ob-servation of elevated antiganglioside antibodies, particularly in the chronic pro-gressive form of MS (166), Pender and colleagues (167) found enhanced T cellreactivity against gangliosides GM3 and GQ1b in PP-MS patients only. Thesefindings suggest that ganglioside-specific T cells can contribute to axonal damagein PP-MS, although further studies are required, particularly with respect to whichcell types and molecular mechanisms are involved in lipid recognition in MS.

ANTIGEN AVIDITY: CROSS-REACTIVITY AND DEGENERACY OF CD4+ T CELL RECOG-

NITION Despite long-held views that cellular immune responses are highly spe-cific, it is now firmly established that the ability of T cells for cross-reactivity ordegeneracy is a normal phenomenon. Degenerate T cell recognition is not onlyrequired for thymic positive selection on thymic self peptides but also for hostprotection against potential antigens that outnumber the available T cells/TCRs byseveral orders of magnitude. For self-antigens expressed in the thymus (e.g., MBP),only T cells recognizing these antigens with low functional avidity are positively se-lected. In agreement, most MBP-specific T cell lines respond to antigen at relativelyhigh concentrations in the micromolar range (69–71, 168), and pathogen-derivedpeptides have been identified that activate MBP-specific TCC at several ordersof magnitude lower concentrations (169). However, high-avidity myelin-reactiveTCC also exist in the periphery, and they are elevated in MS patients comparedwith controls (108). Furthermore, during a trial with an APL peptide derived fromMBP(83−99), we identified TCC responding to both the APL peptide and MBP(83−99)

at subnanomolar concentrations (101), and one of these TCC was present in the pe-ripheral blood already seven years before the APL trial (107). It is not clear whetherchanges in functional avidity occur during the disease process in the periphery,either by changes in the requirements for costimulation or the TCR-associatedsignaling machinery, or whether high-avidity T cells pass “thymic inspection” be-cause central tolerance is less stringent in MS. With respect to self-antigens thatare not or are barely expressed in the thymus, such as MOG or the full length PLPisoform, it is expected that autoreactive T cells are deleted less efficiently in thethymus. This has been confirmed for PLP(139−154)-specific T cells in SJL/J mice.Furthermore, the six myelin peptides (three MBP, one PLP, and two MOG peptides)

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that are immunodominant for high-avidity T cells are either derived from proteinsthat are not expressed in the thymus (PLP(139−154) and the two MOG peptides)or that reside in areas that poorly bind to the MS-associated HLA-DR (108).

Recent observations suggest that the extent of cross-reactivity increases ei-ther during the disease process, upon entering of the CNS/CSF, or during long-term antigen stimulation within the CNS. CSF-derived and clonally expandedTCC during disease exacerbation show a considerably higher degree of cross-reactivity/degeneracy than previously studied peripheral blood-derived TCC (M.Sospedra, unpublished observation; 169, 170). Some of these TCC further demon-strate a high degree of promiscuity in HLA restriction, i.e., restriction by bothMS-associated DR and DQ molecules (M. Sospedra, unpublished observation).

HLA-RESTRICTION AND FUNCTIONAL CHARACTERISTICS OF AUTOREACTIVE CD4+T CELLS Most myelin-specific CD4+ T cells are restricted by HLA-DR molecules(68, 69, 71, 116–118, 121, 168, 171). MBP-specific T cell lines are mainly restrictedby MS-associated DR alleles (Figure 3), and the immunodominant peptides areeither promiscuous binders to all of them [MBP(83−99)] or are recognized with oneHLA molecule, e.g., MBP(111−129) with DRB1∗0401 (121). Investigators do notcurrently know what accounts for these parallels, but the peptide binding character-istics of the disease-associated class II alleles, as well as the preferential generationof certain protein fragments by the processing machinery, are probably important.A few myelin-specific T cell lines have been restricted by DQ or DP molecules(68, 71), although the reasons are not clear. Nonetheless, the observation thatmyelin-specific T cells in Japanese patients with Asian-type (optico-spinal) MSwere in part HLA-DP5-restricted supports the notion that important interactionsoccur among specific HLA class II molecules, T cell response, and disease char-acteristics, because HLA-DP5 is associated with Asian-type MS (172). Anotherstudy suggests that HLA-DP can be relevant for epitope spreading in MS (173).

With respect to function, the aggregate data support the idea that myelin-specificT cells are skewed toward a Th1 phenotype (72, 108, 111, 132, 174). It is importantto consider the methodology of the respective study and the patients’ disease stateand subtype. Fluctuations of cytokine secretion have, for example, been linkedto the MRI-documented inflammatory activity, and elevated expression of IFN-γand TNF-α and reduced IL-10 have correlated with disease activity (175). Eventhough inflammation decreases during SP-MS (Figure 1), the secretion of proin-flammatory cytokines IL-12, IL-18, and IFN-γ are elevated during later stages(176, 177), the activation of Th1 cells is less strictly controlled, and Th1 markersCCR5 and TIM-3 are upregulated (178, 179). When the specificity and cytokineexpression of high-avidity T cells has been linked to MRI characteristics in MS pa-tients, correlations have been observed between MOG-specific Th0/2 cells and lessinflammation, as well as between MBP-specific Th1 cells and a more destructivedisease process (108).

The cytotoxic activity of CD4+ T cells is relatively poorly understood comparedwith that of CD8+ T cells. MBP-specific CD4+ T cells mediate both perforin- and

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Fas/Fas-L-mediated cytotoxicity of MBP or MBP peptide–pulsed targets. Whencomparing MBP-specific T cells restricted by either DR2a or DR2b, only theformer employ perforin-mediated killing or are noncytotoxic, whereas DR2b-restricted T cells exclusively exhibit Fas/Fas-L-mediated cytolysis (122, 171, 180,181). Currently, it is not known how this relates to the pathogenesis of MS. It isunlikely that direct lysis of oligodendrocytes, and even fewer neurons, involvesCD4+ T cells because neither type of CNS cells express HLA class II. A sub-type of MBP-specific CD4+ TCRaβ+ T cells expresses the neural cell adhesionmolecule family member CD56 (also a marker for NK cells) and is capable oflysing CD56+ target cells via homotypic CD56-CD56 interactions independentof HLA restriction (180). A number of CNS cells, including oligodendrocytes,express CD56, and CD4+ CD56+ T cells can indeed lyse oligodendrocytes in anHLA-unrestricted fashion (182).

Furthermore, the requirement for costimulation, i.e., the interaction of CD80/86on APCs with CD28 on T cells, as well as the control via the negative costimulatorCTLA-4, is perturbed in CD4+ T cells in MS. CD4+ myelin-specific T cells, aswell as T cells with specificity for other antigens, are less dependent or independentof costimulation (183–186), and they do not respond, or respond less, to CTLA-4(185, 187). The latter is due to the absence of CTLA-4 upon activation on CD4+

CD28− T cells. Furthermore, this cell population is characterized by a clear Th1skew, seemingly increased proliferative capacity, and relative enrichment for au-toreactive T cells (185). The susceptibility to activation-induced cell death viaFas/Fas-L interactions is not generally impaired. However, data—including theincreased expression of the antiapoptotic molecules survivin, bcl-2, and inhibitorof apoptosis (IAP) family members IAP, IAP-2 and X-IAP in MS T cells, theirheightened expression during disease exacerbations, and downregulation by IFN-β—all suggest that the regulation of apoptosis is perturbed in MS, although someaspects are not different from controls.

CD4+ immunoregulatory T cells (Tregs) are characterized by CD25high expres-sion and the transcription factor Fox-P3 (188, 189). CD4+CD25+ Tregs suppressT cell proliferation by both cell-cell contact- and cytokine-mediated mechanisms.The number and function of CD4+CD25+ Tregs appear reduced in MS patients(190). CD4+ Th2/3 cells and their cytokines IL-4, IL-10, and TGF-β are probablylargely beneficial in MS (191); however, under certain circumstances Th2 cellscan induce EAE (192), and Th2-controlled cell populations, e.g., mast cells, cancontribute to tissue damage in MS.

TCR REPERTOIRE Early EAE studies have demonstrated a restricted TCR reper-toire in some models. Initial data in MS patients appeared to confirm these data,and a restricted expression of Vβ17 was described (193); however, this particularreport was heavily influenced by data from one individual. Subsequent researchhas described a restricted TCR repertoire either within single MS patients, butnot interindividually (194), or across the entire MS populations (195), or not(196). Among the most often found Vβ chains are Vβ5.2, Vβ5.3, and Vβ6.2

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(117, 195, 197), or in PLP-specific T cells Vβ2 (136). Subsequent studies haveexamined CD3 spectratypes or oligoclonality by single-strand conformationalpolymorphism typing and sequencing (136, 197–201). They described (a) an as-sociation of oligoclonal TCR CDR3 spectratypes, particularly in Vβ5.2 T cells(200); (b) prevalence of TCR Vβ13-associated junctional sequences at disease on-set (198); (c) increased MBP reactivity and IFN-γ and IL-2 secretion in CD4+ andCD8+ T cells with altered CD3 length distributions (199); (d) an oligoclonal ex-pansion of T cells with distinct TCRs in the CSF (201; M. Sospedra, unpublishedobservation); and (e) the observation of Vβ5.2-associated junctional sequencesfrom MS brain–derived TCRs similar to an MBP TCC (117, 197), as well asCDR3 motifs in PLP-specific T cells that showed homologies with TCRs fromMS brains (136). Finally, the comparison of the TCR Vα chain usage in monozy-gous concordant and discordant twins showed that the overall TCR Vα chainrepertoire in discordant twins is different, and not only in MBP-specific but alsoin tetanus-specific T cells (202). A recent study that focused on the CDR3 spec-tratypes in naive T cells of discordant monozygous twins found similar distortionsin both the healthy and diseased twin (203). Such repertoire shifts in naive T cellsmay predispose one to MS development, but they are probably not sufficient.

CD8+ T Cells

Much less is known about CD8+ T cells than CD4+ T cells, not only in MSbut in other human autoimmune diseases as well. Technical difficulties in grow-ing and characterizing CD8+ TCC have probably contributed to this temporaryneglect. In the context of effector functions, however, CD8+ T cells are muchbetter suited than CD4+ T cells to mediate CNS damage for the following reasons:(a) Except for microglia, none of the resident CNS cells express MHC class II; itcan be induced on astrocytes by IFN-γ (32), but not on oligodendrocytes or neu-rons, and therefore the latter can only be recognized by CD8+ T cells (204, 205);(b) prominent oligoclonal expansions of CD8+ memory T cells have been foundin the CSF (31) and in MS brain tissue (206), and a persistence of CD8+ TCCin CSF and blood (206); (c) CD8+ T cells are more prevalent in MS brain tissuethan are CD4+ T cells (207); (d) MHC class I can be induced on neurons thatare functionally compromised (208), and CD8+ virus-specific T cells can directlylyse neurons via Fas/Fas-L-mediated cytolysis (205); (e) a number of HLA classI–restricted myelin epitopes have been described for MBP, PLP, MAG, and others(110, 209–211), and the CD8+ cytotoxic T cell response to MBP is increasedin MS patients (211); (f) CD8+ myelin-specific T cells secrete chemoattractants(IL-16 and IP-10) for CD4+ myelin-specific T cells (212); and (g) the MBP(79−87)-specific CD8+ TCC from wild-type C3H mice are encephalitogenic and induce adisease phenotype that resembles MS more closely with respect to the presence ofataxia and spasticity than some of the CD4+ T cell–mediated EAE models (10)(Figure 2). Further data supporting a role for CD8+ T cells in MS are the increasedproduction of lymphotoxin (LT) in SP-MS patients, their increased adhesion to

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brain venules, an increased frequency of CD8+ T cells against EBV epitopes inMS patients, and a correlation between cytokine production by CD8+ T cells andMRI-documented tissue destruction (213). Taken together, there is little doubt thatboth CD4+ and CD8+ T cell responses contribute to MS pathogenesis, albeit atdifferent steps and with different roles.

B Cells and Antibodies in MS

The observation that Igs are elevated in the CSF of MS patients (214) has been themost important and earliest evidence suggesting a role for B cells and antibodies inthe pathology of MS. The correlations between increased CSF Ig with episodes ofworsening and the absence of OCB in some patients with benign MS also suggestthe involvement of humoral responses.

B cells do not cross the intact BBB; however, once inflammation has started,B cells, antibodies, and complement can enter the CNS. The observation of in-creased Igs in the CSF in MS patients (214), but not in the serum, indicates local pro-duction. B cell activation can occur because of stimulation with antigen from eitherself or foreign proteins, through a random bystander effect during inflammation inMS lesions, or by superantigen stimulation. Sequence analysis of the Ig variableregions have shown a high frequency of clonally expanded memory B cells that ex-press variable heavy chain-4 type in MS CSF (215) and also in lesions (216, 217),which suggests selection by a specific antigen. In addition, CSF Igs of MS patientsshow an oligoclonal distribution, i.e., only a limited number of B cell clones con-tributes to the increased CSF Igs (218, 219). B cells and antibodies can contribute toMS disease pathogenesis in various ways. (a) B cells can serve as APCs for autore-active T cells. Supporting this mechanism is the observation that the epitope speci-ficity of the antibodies generated during EAE, the encephalitogenic T cell epitopes,and the immunodominant T and B cell epitopes in humans often overlap (220, 221).(b) B cells provide costimulation to autoreactive T cells. (c) B cells and tissue-bound Ig can recruit autoreactive T cells to the CNS (222). (d) Idiotope-specificT cells may be activated by CSF Igs, and these T cells sustain B cells that pro-duce such idiotopes (164). (e) The production of myelin-specific antibodies andthe destruction of myelin within plaques appear to be the most important way thatB cells contribute to pathogenesis.

In 1959, investigators demonstrated that humoral factors may have a role in in-flammatory demyelination by the in vitro demyelinating activity of a serum factor(223), which was later identified as myelin-specific Igs. Further support came fromhistopathological studies of CNS tissue and the analysis of CSF. B cells, plasmacells, and myelin-specific antibodies are detected in MS plaques and in areas ofactive demyelination in MS patients (224–226). Antibodies can cause demyeli-nation by opsonization of myelin for phagocytosis (227–229). Another antibody-mediated mechanism of demyelination acts via complement activation, leading tomembrane attack complex (MAC) deposition and complement-mediated cytolysis(230). Studies of MS lesions found complement in areas of active demyelination

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(5, 231), and neurological disability and terminal complement concentrations inCSF correlate in MS (232). MAC-enriched vesicles in MS CSF support this mech-anism (233). The demyelinating potential of antibody in EAE has been corre-lated with complement fixation, and soluble complement receptor inhibits EAEseverity.

The antigen specificity or specificities of CSF antibodies in MS has yet tobe established. Most of the CSF OCB are not directed against the major myelincomponents (234), but sometimes against infectious agents (235). Several com-prehensive reviews have been published on this subject (236–238), and belowwe emphasize recent data. Assuming a pathogenic role of autoantibodies in MS,the search for autoantigens has focused on myelin proteins and other CNS com-ponents. A pathogenic contribution of MBP-specific antibodies in EAE has notbeen established, and is controversial in MS. Although some studies emphasizethe relevance of MBP-specific antibodies (239, 240), others fail to confirm thesedata. Unbiased screenings of antigen libraries with CSF Igs did not identify MBPepitopes (241). Technical considerations, as well as the low-affinity interactionsof these antibodies (242), contribute to the controversial results. Increased num-bers of anti-PLP-secreting B cells have been detected in the CSF of MS patients(243), and those with a prominent anti-PLP response are distinct from patientswith anti-MBP antibodies (244). Igs against minor myelin components have alsobeen shown. MOG is the most interesting candidate B cell autoantigen in MS.Anti-MOG antibodies are able to cause myelin destruction in EAE (245–248), incontrast to anti-MBP or -PLP antibodies (249). Anti-MOG antibodies have alsobeen found in human MS lesions (226). The B cell response to MOG is enhancedin MS (145, 250). Serum anti-MOG antibodies in patients with first CNS symp-toms of MS and MRI lesions are predictive of subsequent exacerbations and thediagnosis of definitive MS (251); however, because anti-MOG antibodies are alsofrequent in controls, important questions remain.

Antibodies with specificity against minor myelin components, other autoanti-gens, lipids, and DNA are summarized in Table 3. The observation that autoan-tibodies against ubiquitous antigens are present in MS suggests that less biasedsearch approaches should be applied. A recent flow cytometry study comparedantibody binding to human cell lines between patients with MS and patients withother inflammatory CNS diseases (252). The study observed antibodies to oligo-dendrocyte precursors without differences between RR-MS and SP-MS. Bindingto a neuronal cell line was increased in SP-MS. Although the antigens targetedby these antibodies have to be elucidated, this approach to identifying accessiblecell surface autoantigens that could mediate demyelination or neuronal damageappears promising. Another unbiased method employs array-based or proteomicstechnologies to characterize autoantibodies directed against candidate antigens incohorts of autoimmune and control patients, as well as in experimental autoim-mune conditions (253).

Interestingly, antibodies may also play beneficial roles in two ways. First, theymay skew the cytokine pattern toward Th2. Rats treated with an encephalitogenic

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TABLE 3 Antibody specificities against CNS components other than MOG and MBP

Target antigen Remarks

Myelin-associated glycoprotein (MAG) Low titers in MS; possible involvement inprogression

Oligodendrocyte-specific protein (OSP) Minor myelin component

2′3′cyclic nucleotide3′-phosphodiesterase (CNPase)

—

Transaldolase-H Oligodendrocyte component

Glyco-shingolipids Lipid component of myelin

Sulfatides Lipid component of myelin

GD1a and GM3 (ganglioside) Lipid component of myelin

Galactocerebroside (Gal-C) Major myelin lipid; anti-Gal-C has demyelinatingactivity in vitro; anti-Gal-C antibodies exacerbateEAE

α-B crystallin (small heath shock protein) Detected in MS sera; isotype prevalencecontroversial

Neurofilament-L (NF-L) Elevated in MS CSF, suggested as indicator ofaxonal damage; elevated in the CSF inprogressive MS

AN2 (oligodendrocyte surfaceglycoprotein)

Expression of AN2 on oligodendrocyte precursorcells suggests involvement in suppression ofremyelination

Nogo-A (neurite outgrowth inhibitor) Anti-Nogo antibodies are frequent in serum andCSF of MS patients, but also in controls

Proteasome (protein complex involved inprocessing and chaperone function)

Anti-proteasome antibodies found in serum andCSF in MS

DNA High-affinity antibodies found in MS CSF; fromthe role of anti-DNA antibodies in CNS lupus, itis speculated that they might bind to neurons andoligodendrocytes

peptide of MBP coupled to monoclonal anti-IgD are resistant to induction ofEAE after sequent challenge with MBP in CFA (254). Second, antibodies againstCNS components, e.g., Nogo-A, can foster myelin repair. IgM antibodies againstcertain CNS antigens enhance remyelination in different animal models of MS(255). Further evidence for a beneficial role of antibodies stems from the use ofpooled intravenous Ig in the therapy of MS (256), which acts through a num-ber of mechanisms, including Fc-receptor blockade, inactivation of cytokines,complement inhibition, blocking of CD4 and MHC, and modulation of apoptosis(257).

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INNATE IMMUNE MECHANISMS IN MS

Innate immune responses involve (a) recognition of conserved molecular struc-tures produced by microbial pathogens via TLRs, cells such as macrophages,neutrophils, and mast cells, and effector mechanisms such as the production oflysozyme, lactoferrin, phagocyte oxidase, and nitric oxide; and (b) the recognitionof molecular structures expressed only on normal, uninfected host cells that serve asindicators of “normality” and inhibit immune activation [NK cells, complement,and receptors of the C-type lectin family (258)]. Although the innate immunesystem’s main role is self-protection and maintenance of homeostasis, innate im-mune mechanisms can in some circumstances result in destructive autoimmunity.We summarize important findings and include observations that suggest a role forNKT cells and γ δ T cells in the pathogenesis of MS.

Toll-Like Receptors (TLR)

TLR function as sentinels by recognizing conserved pathogen-associated molecu-lar patterns and generating proinflammatory signals that initiate adaptive immuneresponses. They are expressed by a wide array of immune and nonimmune cells.Inappropriate TLR signaling may contribute to diseases such as MS. TLR engage-ment on dendritic cells (DCs) inhibits immunosuppressive effects of CD4+CD25+

regulatory cells on effector T cells via IL-6 (259), and mice deficient in IL-6 aremore resistant to induction of autoimmune diseases (260). TLRs could further playa role by breaking peripheral tolerance to self-antigens during chronic infections.Assuming that autoreactive T cells are part of the normal T cell population andtightly regulated, it has been hypothesized that tolerance is maintained in a similarmanner to mature T cells after recognition of antigen presented by resting or in-activated DCs (261). Under normal conditions, APCs remain in their resting stateand induce tolerance in autoreactive T cells, whereas danger signals activate APCsand may convert tolerized autoreactive T cells into effector cells. The increase ofMS exacerbations around viral infections supports this concept (56), and pretreat-ment of mice with bacterially derived DNA exacerbates EAE (262). In a recentEAE study, the stimulation of TLR9 with CpG oligonucleotides breaks toleranceand renders lymph node cells reactive against a self-antigen to which they werepreviously unresponsive (86, 263).

Mast Cells

Mast cells are activated during allergic reactions through crosslinking of surfaceIgE receptors, which leads to degranulation of multiple mediators. Mast cellsare ubiquitously distributed among tissues including the brain, but their numbersin the CNS are low and their role unclear. Investigators have suggested severaleffects of mast cells in MS (264). Elevated numbers in MS plaques were originallyshown in 1890 (265) and later confirmed by others (266). They are attracted to MSlesions via chemokines. RANTES, a potent attractant for mast cells, is elevated in

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MS lesions (39). Interestingly, mast cell–released mediators such as tryptase andhistamine are increased in the CSF of MS patients. Gene expression profiling ofMS plaques also demonstrated elevated expression of mast cell mediators in acutelesions (36). Mast cells and their mediators can act in MS during BBB openingand augment CNS infiltration via increased recruitment, adhesion, rolling, andextravasation of leukocytes through the chemokines/cytokines lymphotactin andIL-16, through TNF-α and IL-1-mediated induction of ICAM-1 and VCAM-1expression, and through the effects of histamine and tryptase on leukocyte rolling.Mast cell proteases such as tryptase and chymase activate matrix metalloproteinase(MMP) precursors, and mast cells can also synthesize MMP-2 and MMP-9 directly.It has been suggested that mast cells may act as APCs and influence MS by shapingTh1/Th2 responses, but a clear demonstration of this role is lacking. Finally, mastcell degranulation in response to MBP can lead to demyelination in vitro viaproteolytic enzymes. Mast cell mediators can participate in the destruction ofoligodendrocytes and neurons. With respect to the gender bias of MS and theelevated inflammatory activity in women, it is interesting to note that mast cellsexpress estrogen receptors.

Nitric Oxide Synthase

Phagocytes (granulocytes and macrophages) are equipped with the enzymatic ma-chinery to generate highly toxic reactive oxygen and nitrogen intermediates, whichexert potent antimicrobial activities. The enzyme inducible nitric oxide synthase(iNOS) generates large amounts of nitric oxide (NO), a short-lived and bioactivefree radical that is toxic to bacteria. NOS has been found in MS lesions, sug-gesting a role in MS pathology (267). Although initial studies have shown thatNO can mediate microglia-induced cytotoxicity (268) and also necrosis of rodentoligodendrocytes (269), the actual role of NOS in CNS injury in MS is not clear.Results from blocking NOS in EAE are not conclusive, and additional data suggestthat NO may even have an antiapoptotic effect or modulate immune response in abeneficial way.

NK Cells

An association between decreased NK cell activity and MS was first reported in1980 (270), and later studies expanded this knowledge (271), although findings re-main controversial. Potential explanations are disease heterogeneity among patientgroups and fluctuations of NK activity and number during the disease course. NKlysis is reduced prior to and during acute exacerbations compared with chronic dis-eases (271, 272) and normal during stable phases. Multi-parameter flow cytometrydemonstrated that NK cells are significantly reduced in MS (273). Furthermore,NK deficiencies exist in peripheral blood, placques, and CSF of MS patients (274).Furthermore, NK cell depletion in two different EAE models exacerbate disease(275, 276), whereas the transfer of in vitro generated NK cells decrease autoimmu-nity (277). NK cells could suppress autoimmunity by cytokine production (IL-5,

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IL-13, TGF-β) or by the induction of target lysis via perforin- and/or TRAIL-dependent mechanisms. Supporting data come from perforin-deficient lpr micethat developed severe autoimmunity (278), and blockage of TRAIL exacerbatedEAE (279). In a recent phase II clinical trial with a humanized monoclonal anti-body against the IL-2 receptor α chain in MS (280), we observed marginal effectson CD4+ T cells but an expansion of CD56bright immunoregulatory NK cells. Therelative and absolute expansion of the latter NK cell population and their increasedperforin expression correlate highly with the reduction of the inflammatory activ-ity, and in vitro experiments demonstrated direct lysis of activated CD4+ T cellsvia perforin (B. Bielekova, unpublished observation). These observations indicatethat NK cells may exert important immunoregulatory functions in MS.

Complement

Complement serves as an auxiliary system in antimicrobial defenses. The humanbrain is considered an immunoprivileged site and separated from the peripheryvia the BBB. Nevertheless, all major CNS cells produce most of the complementproteins. Astrocytes are the main CNS complement source, thus providing immunedefense against pathogens, and also contributing to damage in some diseases.Demyelination not only results from an autoimmune response against myelin viathe classical pathway, but also from direct complement activation after binding ofcomplement to myelin. Purified CNS myelin, but not PNS myelin, can activatethe classical pathway (281). Furthermore, mature rat oligodendrocytes are lysedin vitro by complement in the absence of antimyelin antibodies (282). MOG maybe capable of binding and activating the C1q component of complement (283)because it harbors a domain similar to the C1q-binding sequence of antibodies.Complement activation results in oligodendrocyte lysis and chemoattraction ofmacrophages. Susceptibility of oligodendrocytes to complement injury could befacilitated by the lack of the protective and ubiquitously distributed complementinhibitors. CR1 (CD35), membrane cofactor protein (CD46), and homologousrestriction factor were not expressed on oligodendrocytes, whereas CD59 showedsubstantial heterogeneity (283, 284).

NKT Cells

NKT cells share characteristics with T and NK cells and play a regulatory role inautoimmunity as well as in immune responses to tumors and infections via secretionof high levels of IL-4 and IFN-γ . Both CD4− and CD4+ cells contain NKT cells,and in humans CD4− and CD4+ cells express a conserved canonical TCRα chain,Vα24JαQ, paired with a selected Vβ11 segment. NKT cells recognize glycolipidspresented by the nonclassical class I–like CD1d molecule (285). A considerablereduction of Vα24JαQ+ cells among Vα24+ cells has been observed in MS blood(286) and confirmed by another group that also showed reduced Vα24 Vβ11+ NKTcells (287). A further study failed to detect decreased NKT cells within Vα24+

cells, but did detect reduced production of IL-4 by Vα24JαQ TCC (288). A role

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for NKT cells in MS is supported by EAE data. An analog of α-galactosylceramide(GalCer), a synthetic glycolipid that binds CD1d and stimulates mouse and humanNKT cells, suppresses EAE by selective IL-4 induction (289). CD4+ NKT cellsare probably the main NKT regulatory population.

γ δ T Cells

γ δ T cells represent another distinct lymphocyte population that mediates hostdefense and immunoregulatory functions. The expression of NK cell inhibitoryreceptors on human γ δ T cells indicates a role for γ δ T cells in tumor immu-nity and autoimmunity. Two main fractions of γ δ T cells have been described.One fraction of γ δ T cells expresses Vγ 1 within epithelial tissues, where it mayprovide a first line of defense against infections and cancer. The second fractionthat expresses Vγ 2 represents the majority of peripheral blood γ δ T cells. Thisfraction infiltrates chronic lesions and is detected in the CSF of MS patients (290,291). Interestingly, oligodendrocytes selectively stimulate the expansion of theVγ 2 subtype of γ δ T cells (292). Limited TCR heterogeneity of CSF-infiltratingγ δ T cells in MS suggests a common antigen reactivity (293, 294). Human γ δ Tcells can lyse oligodendrocytes via perforin without the need for APCs, possiblythrough recognition of heat shock proteins (291, 295), αB crystallin, or even non-peptide antigens (296). These findings, together with EAE studies in which γ δ Tcells appear to be important early mediators of damage (297), support a role forγ δ T cells in MS pathogenesis.

CYTOKINES AND CHEMOKINES IN MS

Cytokines

Cytokines orchestrate all phases of immune responses, act in highly complex, dy-namic networks in paracrine and/or autocrine fashion, and often exert overlappingand in part redundant functions via multi-component receptor molecules that maybe shared by different cell types. To maintain homeostasis, a dynamic balancebetween pro- and anti-inflammatory cytokines is required. Proinflammatory cy-tokines are thought to play a role in the pathogenesis of MS via immune systemactivation in the periphery and/or by directly damaging the oligodendrocyte/myelinunit. Anti-inflammatory cytokines, e.g., IL-4, have been considered beneficial. Wesummarize the main findings about proinflammatory cytokines (IFN-γ , TNF-α,IL-12, and IL-17), anti-inflammatory cytokines (IL-4, IL-10), and others exertingboth effects (IL-6) in MS (298). Proinflammatory cytokines can participate in thepathogenesis of MS at different points. Elevated numbers of blood cells expressingTNF-α mRNA (299), serum TNF-α concentrations (300), and PBMC secretingTNF-α (301) have been reported in MS patients. Nevertheless, the therapy with asoluble TNF-α receptor Ig fusion protein or anti-TNF-α leads to increased and pro-longed MS exacerbations (302). Results about IFN-γ in the blood of MS patients

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are conflicting. Although higher numbers of PBMC expressing IFN-γ mRNAand serum levels (300) have been found in MS, other studies found no differ-ences (303). A therapeutic trial with IFN-γ in MS resulted in disease exacerbation(304). The role of IFN-γ in EAE is also not clear. The prevailing perception isthat IFN-γ -secreting T cells are encephalitogenic, but IFN-γ -knockout animalsdevelop much worse or even lethal EAE compared with wild-type littermates. IL-12, a main stimulator of IFN-γ has been implicated as a proinflammatory cytokine(305), but recent data indicate that IL-23, a cytokine that shares the p40 chainwith IL-12, is the main mediator of these effects (306). In MS, some studies havereported higher numbers of PBMC expressing IL-12 p40 mRNA (307), but otherstudies found no differences (308).

Data about anti-inflammatory cytokines in MS are similarly contradictory. De-creased numbers of PBMC secreting IL-10 and lower serum levels of IL-10 inMS have been reported (309). Moreover, investigators have described decreasesin IL-10 expression but elevated numbers of PBMC expressing IL-10 mRNA be-fore clinical relapses (310). Therefore, the role of IL-10 in MS is currently notclear. Increased levels of IL-6, a cytokine with pro- and anti-inflammatory ca-pacities, have been shown in MS patient serum (301). Within the CSF and brain,proinflammatory cytokines can damage the oligodendrocyte/myelin unit. Highernumbers of mononuclear CSF cells expressing TNF-α and IFN-γ have been de-tected in MS patients. TNF-α has proinflammatory functions but is also involvedin tissue repair in the brain. Proinflammatory cytokines have also been foundin active MS lesions (311, 312). The expression of TNF-α is elevated in activedemyelinating lesions compared with inactive/remyelinating lesions (313), andtransgenic mice overexpressing TNF-α and IFN-γ driven by the astrocyte-specificGFAP promoter induced demyelination (314). Investigators have proposed differ-ent mechanisms for this demyelination: (a) TNF-α and IFN-γ may be toxic foroligodendrocytes; (b) cytokines may activate macrophages and microglia, whichthen phagocytose myelin; and (c) proinflammatory cytokines may be involved inapoptosis induction/execution and subsequent demyelination. The addition of IFN-γ to cultured oligodendrocytes renders them susceptible to Fas ligand–mediatedapoptosis by inducing Fas expression on their surface (315). The proinflammatorycytokines IL-12 and IL-17 are also elevated in CSF and brain lesion of MS patients(36).

Unexpectedly high numbers of cells expressing IL-4 mRNA have been observedin MS CSF lesions (316). Studies on IL-10 and IL-6 have been contradictory.Assuming a beneficial role of the Th2 cytokines, at least two interpretations can beproposed: (a) These cytokines, mainly IL-10, could be involved in MS pathogenesisby augmenting B cell proliferation, differentiation, and antibody production. Inline with this hypothesis, a correlation between IL-10 levels and IgG in the CSFof MS patients has been reported (317). (b) The presence of IL-4, IL-10, andTGF-β in CSF or MS brain parenchyma could reflect ongoing immunoregulatorymechanisms that are initiated after disease exacerbations and are important fordisease resolution/prevention in EAE (318).

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Chemokines

Chemokines and their receptors play a central role in the inflammatory recruit-ment of leukocytes and other cell types. Trafficking of inflammatory T cells intothe CNS is a crucial step in MS and begins with weak adhesion and rolling onthe endothelium of the BBB, followed by firm arrest on the luminal side of theendothelium and subsequent diapedesis across the BBB. Chemokines induce andactivate leukocyte adhesion molecules that mediate firm adhesion to the endothe-lium and establish a chemotactic concentration gradient that results in recruitmentacross the endothelial monolayer. The induction of proteolytic enzymes facilitatesBBB opening (319), and subsequently chemokines mediate retention of leukocytesin the CNS. Numerous reports analyze the roles of chemokines and their receptorsin intrathecal accumulation of T cells in MS (320). Among the various chemokinereceptors, CCR5 and CXCR3 have received attention as key receptors on Th1 cells,as have CCR3 and CCR4 on Th2 cells. Furthermore, CCR7, an important markerfor the capacity of mononuclear cells to migrate to secondary lymphoid organs, isalso of interest. This section summarizes the main findings on chemokines in theblood, CSF, and lesions in MS.

BLOOD CCR5 expression is increased on circulating T cells in MS patients (321,322) and during disease relapse, suggesting a pathogenic role of CCR5+ T cells(323). Increased CXCR3 expression on circulating T cells has been shown in somebut not all studies (322). T cells expressing CCR5 and CXCR3 in MS produce highquantities of IFN-γ and TNF-α (324), and MBP-specific Th1 cells express highlevels of CXCR3 and CXCR6 (325). The effects of IFN-β treatment on chemokineand chemokine receptor expression are controversial.

CSF CCL5 (RANTES) and CXCL10 (IP-10) are elevated in MS CSF, whereasCCL2 (MCP-1) is significantly decreased (326). The increase of CXCL10 (IP-10)and decrease of CCL2 (MCP-1) has been confirmed to take place during MS exac-erbations and not to occur during remissions (327). CCL2 (MCP-1) decreases cor-relate with active MRI, i.e., presence of inflammation and gadolinium-enhancinglesions in the brain (328), suggesting a Th1 polarization in active MS. CCL3(MIP-1α) has been found in the CSF of MS patients, as well as in other neuroin-flammatory diseases. The source of these chemokines in the CSF remains to beelucidated.

With respect to chemokine receptors, initial studies document a higher propor-tion of CSF T cells that express CXCR3 and CCR5 (326) compared with PBMC.Because CSF T cells are enriched for the CD4+/CD45RO+ subset, corrections forthis bias have shown that only CXCR3, but not other receptors (CCR1-3, CCR5,and CCR6), is relatively increased on CSF (329). Interestingly, the same has beenobserved in controls and interpreted such that the presence of CXCR3+ cells inthe CSF is independent of CNS inflammation (326). CXCR3 expression probablyfacilitates the entry of T cells into the CSF, and CXCL10 (IP-10) mediates the

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retention in the inflamed CNS. CCR5+ and CXCR3+ Th1 cells in the CSF alsoexpress CCR7 (330), and CSF-infiltrating monocytes express higher CCR1 andCCR5 levels (331). But similar results were obtained in controls, suggesting thatthe presence of CCR1+/CCR5+ monocytes in the CSF is independent of CNSinflammation.

BRAIN LESIONS A number of chemokines and the corresponding receptors havebeen detected in MS brain lesions, indicating that they might evolve into interestingtherapeutic targets. CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES) areexpressed within MS lesions, CCL4 in parenchymal inflammatory cells (macro-phages and microglia), CCL3 also in parenchymal inflammatory cells and activatedneuroglia (332), and CCL5 in perivascular inflammatory cells and (though less so)in astrocytes (39, 332, 333). Other chemokines in active MS lesions include CCL2(MCP-1), CCL7 (MCP-3), CCL8 (MCP-2), and CXCL10 (IP-10). CXCR3 is ex-pressed on the majority of perivascular T cells in MS brain lesions, and CCR5 on asubset of these cells. CCR1 has been found on newly infiltrating monocytes (331),CCR2 and CCR3 on macrophages (333), and CCR5 on infiltrating monocytes andactivated microglia cells (324, 326, 333).

A role for chemokines and their receptors in MS is supported by EAE data.Increased expression of CCL2, CCL3, CCL5, and CXCL10 in EAE is associatedwith disease progression, and in vivo depletion improves EAE (334). Mice deficientin CCR2 (335), and to a lesser extent in CCR1 (336), fail to exhibit EAE symptoms.In contrast, CCR5-deficient mice showed similar disease severity than controls(337), which suggests that T cell accumulation in the CNS during EAE does notfunction through CCR5.

Polymorphisms in genes for chemokines and their receptors have been proposedto confer susceptibility or protection in MS, although definitive evidence is stilllacking. The CCR5 �32 mutation leads to a nonfunctional receptor that has beenassociated with decreased severity of MS. Although homozygous individuals forCCR5 �32 were not protected from MS, heterozygosity for �32 has been linkedto prolonged disease-free intervals and a delay in MS onset. Microsatellite poly-morphisms in CCL7 (MCP-3) have also been associated with disease resistanceto MS.

PATHOGENETIC STAGES IN THE DISEASE PROCESSIN MS: LESION PATHOLOGY

Figure 4 summarizes the most important events in MS. Potentially autoreactiveCD4+ T cells are activated in the periphery by recognizing, for example, a vi-ral peptide in the context of costimulatory and other less-defined signals (step1). Factors that contribute to a proinflammatory environment include a numberof cytokines from both T cells and APCs (e.g., IL-12, IFN-γ ), the strength ofactivation, and the infectious context (“danger”). Activated autoreactive T cells

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Figure 4 Schematic diagram depicting the pathogenetic steps and contributing factors thatlead to tissue damage in MS (see text for details).

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adhere to the BBB endothelium via adhesion molecules (LFA-1 and VLA-4), andtransmigrate into the brain parenchyma through cerebrovascular endothelial cells(step 2). Several mechanisms are still unclear, including what guides autoreactiveCD4+ T cells to the CNS; whether antigen presentation is required in deep cervi-cal lymph nodes, a putative draining site for brain-derived antigen; and whethera chemokine gradient from inside the brain parenchyma to the blood exists dur-ing the initial event. However, experiments in EAE have shown that adoptivelytransferred encephalitogenic T cells are transiently found in deep cervical lymphnodes and then locally reactivated in the CNS, as shown by downmodulation oftheir TCR (338). Subsequently, proinflammatory cytokines (IFN-γ , IL-23, TNF-α, LT) and chemokines (RANTES, IP-10, IL-8, and others) (a) activate residentcells, such as microglia and astrocytes; (b) recruit other immune cells, includingmonocytes, CD8+ T cells, B cells, and mast cells, from the peripheral blood; and(c) orchestrate the formation of the inflammatory lesion (step 3) . The formation ofthe inflammatory lesion is characterized by an open BBB with tissue edema aftermediator/protease release from mast cells, monocytes, and T cells, as well as by ahost of proinflammatory molecules and oxygen and nitrogen radicals. Damage ofCNS tissue, i.e., the myelin sheath, oligodendrocytes, and axons, occurs alreadyat this early inflammatory stage (step 4). During the above steps, CD4+ autoreac-tive T cells are likely driving the process, whereas their role in the effector phaseis probably secondary. Numerous processes may lead to myelin/oligodendrocyteand axonal damage, including radicals, TNF-α, LT, and direct complement deposi-tion, as well as antibody-mediated complement activation and antibody-dependentcellular cytotoxicity via Fc-receptors, myelin phagocytosis, direct lysis of ax-ons by CD8+ cytotoxic T lymphocytes, the secretion of proteases, and apoptosisof oligodendrocytes. However, the increased production and decreased degrada-tion or reuptake of the excitatory neurotransmitter glutamate by astrocytes leadsto glutamate-mediated excitotoxicity of oligodendrocytes via glutamate receptor-mediated calcium influx (12). The inflammatory event lasts from a few days totwo weeks. The “aftermath” is characterized by stretches of demyelinated axons,apoptotic oligodendrocytes and T cells, axon transsections with onion bulb-likeprotrusions owing to interrupted axonal transport (339) (Figure 1), macrophagesloaded with phagocytosed myelin lipids, and the activation and beginning pro-liferation of astrocytes. Besides clearing debris, lesion resolution (step 5) furtherincludes a relative dominance of Th2/Th3 cytokines such as IL-10 and TGF-β, andthe secretion of various growth factors (brain-derived neurotrophic factor, platelet-derived growth factor, ciliary neurotrophy factor, and fibroblast growth factors) byboth resident cells and T cells. Oligodendrocyte precursors that are still presentin the adult CNS are also activated, and surviving oligodendrocytes begin to re-myelinate denuded internode areas, although the original thickness of the compactmyelin is not reached again and hence nerve conduction velocity is slower in these“repaired” areas, despite some compensatory redistribution of sodium channels.Inhibitory signals between axonal and myelin structures, including Nogo, MAG,and OMgp, all of which interact with Nogo receptors and are physiologically

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relevant during shaping and maintenance of the intricate cytoarchitecture in theCNS, impede the repair process (340). “Repaired” myelin differs from matureadult myelin in its relative composition of myelin protein isoforms and/or post-translational modifications. The relative abundance of citrullinated C8-MBP isone example. C8-MBP is less basic than mature MBP owing to modification of sixarginines into citrullines (341). C8-MBP increases during the course of MS andprobably results in functionally impaired myelin, as well as in increased vulnera-bility to further damage (342). C8-specific T cells have been found in MS patients.During the months and years following an inflammatory event, the cellular compo-sition of the plaque changes dramatically. Chronic plaques may show smolderinginflammation, but they are often devoid of inflammatory cells and characterizedby loss of myelin and axons, relative increases in astrocytes (but overall lowercellularity), and deposition of scar tissue.

The cellular composition and involved molecular pathways vary among patients(5). Besides the recognition of pathological heterogeneity, other “forgotten” as-pects, such as axonal injury, have received new attention (339). Investigators haveidentified four pathologic MS subtypes on the basis of the relative contributionof different immune cells, antibody and complement deposition, myelin loss, andoligodendrocyte death (5). Interestingly, patterns differ interindividually, but notintraindividually. The following pathologic subtypes are described by Bruck andcolleagues (343):

Pattern I. This pattern is predominated by T cells and macrophages, andcandidate effector molecules include TNF-α, IFN-γ , and radical species.

Pattern II. In this pattern, antibody and complement deposition predominate,and both MOG- and MBP-specific antibodies are involved. The mechanismof tissue destruction shares similarities with those observed in Guillain Barresyndrome, an acute inflammatory demyelinating disease of the PNS.

Pattern III. Lesions impress by preferential loss of MAG and oligoden-drogliopathy, and a vasculitic mechanism is suspected on the basis of parallelswith focal cerebral ischemia. Furthermore, the vulnerability of oligodendro-cytes may be increased by immune responses against heat shock proteins inthis pattern.

Pattern IV. This pattern, marked by nonapoptotic oligodendrocyte degenera-tion, is the least common and occurs primarily in PP-MS (343). The overallextent of inflammation is highest in RR-MS and declines over time, with theevolution into SP-MS (Figure 1).

Further pathologic observations that deserve mention include the axonal loss,which was originally described by Charcot (92) and others in the mid-nineteenthcentury. Substantial axonal loss may occur during the earliest stages of disease.It is closely related to neurological disability, and, as mentioned above, severaleffector mechanisms, including antiganglioside antibodies and CD8+ CTL, areprobably involved. Finally, a number of findings indicate that contributors totissue vulnerability and aberrant repair include the vulnerability of CNS tissue,

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the local dysregulation of apoptosis mechanisms such as higher expression ofbcl-2 on oligodendrocytes during RR-MS, glutamate-mediated excitotoxicity (12,344), and the reexpression of developmentally important recognition molecules(Jagged1/Notch) (13).

LESSONS FROM THERAPIES

The concept of MS as an autoimmune inflammatory disease is supported by theresponse to immunomodulatory and suppressive treatments. Glucocorticoids, ap-plied intravenously and at high doses during acute clinical exacerbations of MS,act broadly as anti-inflammatory agents by reducing edema and arachidonic acidmetabolites and by decreasing and modulating IL-1, IL-2, IL-4, IL-5, IL-6, IFN-γ ,TNF-αβ, fibrin deposition, and other mechanisms.

A number of chemotherapeutic agents with similarly broad activities but long-term immunosuppressive effects are used at more advanced stages of the disease,i.e., the transition from RR-MS to SP-MS, or in patients with aggressive diseasewho do not respond or who incompletely respond to the approved agents. Im-munosuppressants include mitoxantrone, cyclophosphamide, methotrexate, aza-thioprine, cladribin, and mycophenolate. Interestingly, their mechanism of actionin autoimmune diseases is relatively poorly understood; however, we do know thatcyclophosphamide not only has apoptosis-inducing activities but also induces Th2cells in MS.

IFN-β is approved for treatment of RR-MS and is currently the agent that is mostbroadly used. It was originally explored as an antiviral agent, but in recent yearsit has been shown that it has immunomodulatory activities. These immunomod-ulatory activities include the upregulation and increased shedding of adhesionmolecules, induction of IL-10 and neurotrophic factors, blocking of BBB openingvia inhibition of MMP-2 and -9, and reduction of cell adhesion to the BBB. IFN-βreduces disease exacerbations by only about 30% and has a modest impact on dis-ease progression. IFN-β is a clear step forward in MS therapy, but the frequency ofsubcutaneous injections of IFN-β, the flu-like symptoms that occur at the begin-ning of therapy, the modest activity required of patients, and the treatment failuresare all reasons to search for better agents.

Glatiramer-acetate (GA, copolymer-1, Cop-1) is another approved therapy forRR-MS, with similar or slightly lower efficacy than IFN-β at high doses. However,GA has a more favorable side-effect profile than IFN-β (345). GA is a randomcopolymer of the four amino acids Ala, Lys, Glu, and Tyr, with various lengths andfixed molar ratios of 4.5:3.6:1.5:1 (346). It was originally developed as a mimic ofMBP and to induce EAE (346). Fortuitously, GA blocks the experimental disease(346). Initially, it was assumed that it acts primarily by displacing autoantigenicpeptides from HLA class II binding grooves, i.e., via competition for binding.Later, a host of other activities were shown, including polyclonal T cell stimulation,partial agonist effects, Th2 activation and cross-reactivity with myelin peptides,shift of the antibody response toward IgG4, interference with DC differentiation,

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and induction of brain-derived neurotrophic factors (347, 348). The most importanteffect of GA is most likely the relative skew toward Th2 reactivity. When inflamma-tory activity is monitored via MRI, IFN-β reduces BBB opening almost immedi-ately, but it takes much longer until an effect of GA is observed. Currently, attemptsare ongoing to develop better defined and more active peptidic compounds.

Other promising therapeutic strategies include humanized monoclonal anti-bodies against VLA-4 (natalizumab), which blocks BBB migration of T cells andtheir activation and reduces brain inflammation (349), and against the IL-2 re-ceptor α chain (daclizumab), which activates and expands immunoregulatory NKcells (280). Daclizumab reduces brain inflammation by almost 80% in patientswith high disease activity who have failed IFN-β treatment (280), but daclizumabis also effective as monotherapy (J. Rose, personal communication). Anti-CD52leads to long-lasting lymphopenia and also reduces inflammatory activity in MS(350). Numerous other monoclonal antibodies (e.g., against CD20+ B cells andCD40L) are either in preclinical or clinical testing. Promising results have alsobeen observed with estriols (51) and the cholesterin-lowering statins (351, 352).

Further strategies include modulators of cAMP levels, e.g., phosphodiesterasetype 4 inhibitor, pentoxifylline (353), and β-adrenergic agents, inhibitors of chem-okine receptors (CCR2 antagonists), blocking agents of CD4, retinoic acid, vita-min A and D derivatives, peroxisome proliferator-activated receptoragonists, DNAvaccination, and numerous others. Many of these agents have appeared promisingin EAE but later not shown activity in MS. For example, the phosphodiesterasetype 4 inhibitor Rolipram had shown prophylactic and therapeutic activity in EAE,but in a recent clinical trial in MS showed no disease reduction (B. Bielekova, un-published observation). Paradoxic effects have been observed with therapies aimedat TNF or TNF-receptors (see above). Furthermore, in rheumatoid arthritis, whereTNF-blocking agents have become standard therapy, a number of cases developedacute inflammatory demyelination or MS. Caution must therefore be used both inextrapolating animal data to humans or information from one autoimmune diseaseto another.

REESTABLISHING TOLERANCE

Reestablishing tolerance to autoantigens and specific and subtle therapeutic inter-ventions remain important goals. The question is whether they can be achieved incomplex and heterogeneous diseases such as MS. Currently, investigators are pur-suing two main lines. The first is modulation of antigen-specific T cell responses viainduction of anergy or activation-induced cell death. The latter is achieved throughintravenous immunization with either autoantigenic peptides, proteins/fusion pro-teins, or DNAs that code for these proteins with and without covaccination withDNAs coding for anti-inflammatory cytokines, or by APL peptides. The secondinvestigative line is methods to induce anti-idiotypic T cells directed either at TCRCDR2 or CDR3 regions of autoantigen-specific TCR chains, or vaccination withwhole, inactivated, autoreactive T cells.

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Currently, it is not clear whether either of these approaches can be successful. Wehave already mentioned the negative experience with a high dose of APL peptide,which not only led to hypersensitivity reactions but also to disease exacerbations(101). Lower doses appeared to induce a Th2 bias, and a currently ongoing trialwith the same APL will hopefully solve whether APL therapy is viable. T cellvaccination (354) or immunization with CDR2 peptides have been well tolerated(355). With respect to their mechanisms, the induction of CDR2-specific T cellsthat secreted IL-10 has been shown (355). T cell vaccination has led to the reductionof MBP-specific T cells, apparently via CD8+ cytolytic T cells, and treatment withanti-Vβ5.2/5.3 led to the reduction of Vβ5.2/5.3-expressing T cells; however, theeffect on reducing MRI activity was below expectations (356). In summary, ourincomplete understanding of antigen-specific T cell responses in MS, the diseaseheterogeneity, and its complex pathogenesis are among the factors that renderspecific immune intervention very challenging.

A more drastic approach toward reestablishing tolerance is hematopoietic stemcell transplantation (HSCT) via abrogation of the hematopoietic or lymphopoi-etic system by chemotherapy/irradiation, or optionally via lymphocyte-depletingsteps such as antilymphocyte antibodies and subsequent infusion of autologoushematopoietic (CD34+) stem cells. Although still considered a high-risk proce-dure, HSCT offers the prospect of stopping the autoimmune process and curing atleast the inflammatory aspects. Recent trials revealed that (a) inflammatory diseaseactivity is completely halted in the majority of patients (357); (b) progression ofclinical disability continues in patients with advanced disease (358, 359) and there-fore HSCT probably must be applied earlier when neurological deficit is limited butthe patient clearly has aggressive disease; (c) low-risk protocols have to be exploredand improved, and such studies are currently ongoing; and (d) long-term followup is necessary, and we need to understand the mechanism of action. With respectto the latter point, HSCT indeed leads to rejuvenation of the immune system, withincreased recent thymic emigrants, reactivation of the thymus, a net increase ofnaive CD4+ T cells, and the reestablishment of a more diverse TCR repertoire.Transiently after HSCT, there is also increased apoptosis of T cells and a relative in-crease of CD4+CD25+ regulatory T cells (P.A. Muraro, unpublished observation).

New approaches toward specific immune intervention clearly need to be defined,but recent progress in immunomodulation has been very promising. We believethat future therapies toward tissue repair and neuroprotection are only meaningfulif the inflammatory components of MS can be contained or completely stopped.

CONCLUDING REMARKS

Exciting progress has been made in understanding MS pathogenesis in the pastdecade. Every aspect has become more complicated, and our previous concept ofMS as “simply” a CD4+ Th1 cell–mediated autoimmune disease must be revisited.We now recognize that the complex genetic background in concert with environ-mental triggers—most likely common viral infections, but mitigated by many

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other factors—is responsible for the heterogeneity of every aspect of the disease,including pathologic mechanisms, clinical and MRI presentation, and response totreatments. Many components of the innate and adaptive immune systems, and inthe latter CD4+ T cells, CD8+ T cells, and antibodies, all contribute to differentaspects of the disease process. In addition, factors other than the autoimmune re-sponse clearly shape the disease. The vulnerability of the CNS to inflammatoryinsult and/or its inability to repair tissue is equally heterogeneous among differ-ent patients, and we will only understand the full scope of disease etiology andpathogenesis if we consider both immune system and nervous system and theirmutual interactions in MS. The latter point is particularly relevant when we tryto block the disease process or even repair already inflicted damage and preventit in the future through single agent, cell-based, or combination therapies. Thesetreatments will likely become much more complex than those currently applied.

APPENDIX

Abbreviations used: αB-C, α-B crystallin; ADCC, antibody-dependent cellularcytotoxicity; APC, antigen-presenting cell; APL, altered peptide ligand; APOE,apolipoprotein E; BBB, blood-brain barrier; CNPase, 2′,3′-cyclic nucleotide 3′

phosphodiesterase; CNS, central nervous system; Cpn, Chlamydia pneumoniae;CTLA, cytotoxic T lymphocyte–associated antigen; DC, dendritic cell; EAE,experimental allergic encephalomyelitis; EBV, Epstein-Barr virus; ELISPOT,enzyme-linked immunospot; GA, glatiramer-acetate; G-CSF, granulocyte colony-stimulating factor; GFAP, glial fibrillary acidic protein; HHV, human herpesvirus;HLA, histocompatibility leukocyte antigen; HSCT, hematopoietic stem cell trans-plantation; HSV, herpes simplex virus; IAP, inhibitor of apoptosis; IFN, inter-feron; IP, IFN-γ -inducible protein; LT, lymphotoxin; MAC, membrane attackcomplex; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MCP,monocyte chemoattractant protein; MHC, major histocompatibility complex; MRI,magnetic resonance imaging; MMP, matrix metalloproteinase; MOBP, myelin-associated oligodendrocytic basic protein; MOG, myelin oligodendrocyte glyco-protein; MS, multiple sclerosis; NO, nitric oxide; NOS, nitric oxide synthase;OCB, oligoclonal bands; OSP, oligodendrocyte-specific glycoprotein; PBMC, pe-ripheral blood mononuclear cells; PLP, proteolipid protein; PNS, peripheral ner-vous system; PP-MS, primary progressive MS; RR-MS, relapsing-remitting MS;SP-MS, secondary progressive MS; TCC, T cell clones; TCR, T cell receptor;TGF, transforming growth factor, TLR, Toll-like receptor; TNF, tumor necrosisfactor; TRAIL, TNF-related apoptosis-inducing ligand; Treg, immunoregulatoryT cell; VZV, varicella zoster virus.

ACKNOWLEDGMENTS

We realize that many studies could not be considered, and we apologize to theauthors of this work. Our summary views try, however, to take them into account.

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I (R.M.) thank Hans-Wolfgang Kreth, MD, Department of Pediatrics, Universityof Wurzburg, Germany, my first teacher in immunology, and Henry F. McFarland,MD, Neuroimmunology Branch, NINDS, NIH, Bethesda, my long-term mentor,for his advice and support. Further, we acknowledge the work of our coworkersand prior investigators at the Cellular Immunology Section and NeuroimmunologyBranch, NINDS, NIH, whose research during recent years has contributed to thisreview.

The Annual Review of Immunology is online athttp://immunol.annualreviews.org

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Mireia Sospedra and Roland Martin - Semantic Scholar...Mireia Sospedra and Roland Martin Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders