Immune Responses Against the Myelin/Oligodendrocyte Glycoprotein in Experimental Autoimmune Demyelination

Special Article

Immune Responses Against the Myelin/OligodendrocyteGlycoprotein in Experimental Autoimmune Demyelination

HANS-CHRISTIAN VON BUDINGEN,1 NAOYUKI TANUMA, 1 PABLO VILLOSLADA, 1,2

JEAN-CHRISTOPHE OUALLET,1,3 STEPHEN L. HAUSER,1 and CLAUDE P. GENAIN1,4

Accepted: January 16, 2001

Myelin/oligodendrocyte glycoprotein (MOG) is a surface-exposed antigen of myelin and an important target for autoim-mune responses which mediate inflammatory demyelination inthe central nervous system. Experimentally, MOG inducesstrong pathogenic T cell responses in many strains of labora-tory animals. Immunological studies in humans also identifyMOG as a surprisingly prevalent antigenic molecule among themyelin proteins. In addition, the encephalitogenic properties ofMOG are linked to the induction of antibody responses whichhave been demonstrated to directly promote central nervoussystem demyelination, a hallmark neuropathological feature indisorders such as human multiple sclerosis. Factors responsiblefor autoimmunity to MOG likely include genetic influences aswell as other mechanisms, which are the subject of intenseinvestigation. This article reviews experimental data currentlyavailable on specificity and pathogenic roles of T cell andantibody responses against MOG, which have implicationsrelevant to multiple sclerosis and related disorders.

KEY WORDS: Autoimmunity; myelin proteins; epitopes; rodents;nonhuman primates.

INTRODUCTION

Multiple sclerosis (MS) is a chronic, inflammatory de-myelinating disorder of central nervous system (CNS)

white matter of unknown etiology, characterized patho-logically by perivascular inflammation, destruction of themyelin sheaths, proliferation of astrocytes with gliosis,and loss of oligodendrocytes and axons (1–3). Studies ofexperimental allergic encephalomyelitis (EAE), an auto-immune CNS inflammatory disorder produced in labo-ratory animals after sensitization with myelin antigens,have provided many of the current concepts used tounderstand the pathophysiology of human MS. In EAE,CNS inflammation is initiated by activation of autoag-gressive, myelin-specific T cells, which disrupt theblood–brain barrier and locally trigger a cascade ofevents that together promote or entertain the tissuedestruction that translate into neurological dysfunction(reviewed in Ref. 4).

After it was discovered that immunization with CNSwhite matter could induce CNS inflammatory demyeli-nation, many investigators seeked to identify a singleantigen responsible for this destructive autoimmune re-sponse. Studies have initially focused on the majormyelin proteins, myelin basic protein (MBP) and prote-olipid apoprotein (PLP) (5, 6). Observations that EAEcould be adoptively transferred by lymphoid cells (7),and the subsequent discovery that encephalitogenic (e.g.,disease-inducing) T cell populations were targeting arestricted repertoire of myelin epitopes, provided furtherimpulse for neuroimmunologists to elucidate the patho-physiologic role of myelin-specific T cell responses inEAE and MS (8, 9). Effector mechanisms of cellularimmunity, for example, proinflammatory cytokines suchas IFN-g and TNF-a, are regarded as major factors thatpromote CNS myelin damage (10) and are targets for

1Department of Neurology, University of California, San Francisco,California 94143. USA.

2Department of Neurology, University of Navarra, Pamplona, Spain.3Department of Neurology, Hopital Tenon, Paris, France.4To whom correspondence should be addressed at NeuroimmunologyLaboratory, Room C-440, University of California, San Francisco.505 Parnassus Avenue, San Francisco, California 94143-0435. Fax:(415) 502 5899. E-mail: [email protected].

Journal of Clinical Immunology, Vol. 21, No. 3, 2001

1550271-9142/01/0500-0155$19.50/0 © 2001 Plenum Publishing Corporation

disease-modifying therapies in MS (11). One looking inperspective at preclinical trials, however, quickly real-izes that therapeutic success in EAE has not been a verygood predictor of efficacy in MS trials. Perhaps thisemphasizes the likelihood that other mechanisms areinvolved in the pathogenesis of autoimmune CNS disor-ders, separately or in combination with autoagressive Tcell responses. Indeed, as suggested by recent analyses oflarge series of biopsy and autopsy material, MS may infact represent a group of very heterogeneous disorderswith distinctive neuropathological features that suggestdifferent pathophysiological mechanisms (12, 13). Thediversity of mechanisms that may result in CNS inflam-matory demyelination is also illustrated by the existenceof many different models of EAE, each characterized byvarious degrees of inflammation and demyelination,depending on the species studied and the method usedfor induction of disease. Thus, while it is established thatcellular autoimmunity most often leads to blood–brainbarrier disruption and perivascular inflammation, patho-genic T cell responses may not necessarily be associatedwith permanent tissue destruction which may requireadditional mechanisms (14).

Long before the discovery of MHC restriction and theelucidation of the trimolecular complex, earlier studies hadsuggested humoral factors as effector mechanisms for im-mune-mediated demyelination (15, 16). It was also recog-nized that the target for these antibody responses wasunlikely to be MBP (17–19). Lebaret al. (20, 21) were thefirst to propose that the prominent demyelination observedin guinea pigs immunized with whole myelin was producedby antibodies to a protein expressed by oligodendrocytes,identified as M2 and different from MBP and the proteo-lipid proteins. The M2 protein was isolated by Liningtonand colleagues in the mid 1980s, with the use of amonoclonal antibody raised against rat cerebellar glycopro-teins and termed myelin/oligodendrocyte glycoprotein, orMOG (22). Although quantitatively minor compared toother myelin proteins, MOG has, within the last decade,emerged as a prime candidate target for pathogenic CNS-specific autoimmune responses.

In murine EAE, the pathogenicity of immune re-sponses to MBP and PLP (which are abundant CNSantigens, together representing.75% of total myelinproteins) is restricted to susceptibility conferred byappropriate MHC class II elements. For example, theSJL/J mouse (H-2s) is responsive predominantly toimmunodominant epitopes of PLP, while the PL/J mouse(H-2u) will respond preferentially to the peptide 1–11 ofMBP. In contrast, MOG or MOG-derived peptides ap-pear to have a strong encephalitogenic potential in mostrodent strains and species studied to date. In addition to

the ability of MOG to produce vigorous CNS-specific Tcell responses (23), numerousin vitro andin vivo studieshave confirmed that anti-MOG antibodies have demyeli-nating properties (24–30). In humans, heightened T cellreactivity to MOG is observed in peripheral blood,compared to MBP and PLP (31–33). Furthermore,MOG-specific immunoglobulin deposition has recentlybeen described within actively demyelinating lesions ofMS and causally associated with irreversible vesiculartransformation of myelin sheaths (34, 35).

These observations highlight the unique antigenicproperties of MOG amongst myelin proteins, the reasonsfor which are not entirely understood. As methods for thepurification of native forms of MOG and the expressionof recombinant MOG have been developed, a substantialamount of information is now available on cellular andhumoral responses against this protein in several species,including mice and rat strains of different genetic back-grounds and outbred nonhuman primates. This articlebriefly outlines the biochemical characteristics of MOG,reviews our current knowledge of B cell and T cellresponses against MOG in EAE, and discusses how thisinformation can be used to better our understanding ofCNS autoimmune demyelination.

BIOCHEMICAL AND BIOLOGICAL PROPERTIES OFMOG (REFER ALSO TO TABLE I)

Cloning of cDNA encoding for MOG in human(36–38), rat (39), mouse, bovine (40, 41), and marsupialspecies (42) has shown that the protein contains 218amino acids with a high degree of conservation acrossspecies and is a member of the immunoglobulin (Ig)superfamily. The genes encoding for MOG have beenmapped at the distal end of the MHC class I region inhuman, mouse, and rat (43, 44). MOG is unique in the Igsuperfamily of proteins, since hydropathicity predictionsshow two hydrophobic domains (39, 45). The firsthydrophobic domain is located between amino acid (aa)residues 122 and 150 and spans the myelin membranelipid bilayer, while the second domain (aa residues174–200) most likely does not span the plasma mem-brane but may be associated with it or embedded withinit (46, 47). MOG contains a possible intracytoplasmicphosphorylation site (Thr 167) and anN-glycosylationsite (Asn 31) within the extracellular domain.In vivo,MOG is glycosylated and has been shown to contain theHNK-1 carbohydrate epitope, as do other members of theIg superfamily (48–50). The structure of MOG has notbeen experimentally obtained and its function(s) is cur-rently unknown, although its sequence and homologycharacteristics suggest that it may act as an adhesion

156 VON BUDINGEN ET AL.


molecule; act as a receptor for complement binding, orparticipate in signaling processes within oligodendro-cytes (42, 51). MOG is developmentally regulated andappears to be a marker of oligodendrocyte maturation(52–55). Expression of MOG outside the CNS has notbeen firmly documented to date, unlike other proteins ofmyelin such as MBP and PLP (56–58).

The extracellular portion of MOG contains the Ig-likedomain, between cysteine residues at positions 24 and98, which suffices for induction of EAE in all specieswhen expressed in nonglycosylated recombinant form inbacteria. Factors that could explain the high encephali-togenicity of MOG include the extracellular location ofthe Ig-like domain and the fact that MOG is expressedlargely on the outermost lamellae of the myelin sheath,where it is accessible to autoimmune attack, especially toautoantibodies (59, 60). In addition, MOG shares a highamino acid sequence homology with other proteins suchas butyrophilin, a protein expressed in the lactatingmammary gland that is encoded by a gene which alsomaps in the MHC region. Autoimmunity triggered bymolecular mimicry is indeed possible in the case ofMOG, as cross-reactivity has been found between MOGpeptides and viral and butyrophilin peptides (61, 62).

MOG-INDUCED EAE IN VARIOUS STRAINSAND SPECIES

MOG was first characterized as an immunodominantautoantigen responsible for the demyelinating antibodyresponse in guinea pig EAE induced by immunizationwith spinal cord tissue in adjuvant (21, 26). Subse-quently, it was also demonstrated, in several species andmultiple antigen systems, that prominent demyelinationcould be induced by exogenous administration of MOG-specific antibodies (25, 27–30).

Several studies have now shown that MOG by itself isable to generate encephalitogenic T cell responses and to

induce EAE in inbred mice, rats, and nonhuman primates(Table II). All investigators used recombinant forms oftruncated MOG encompassing the Ig-like extracellulardomain (rMOG), with the exception of Johnset al. (63),who employed native MOG (aa 1–218) purified tohomogeneity to immunize Lewis rats in the absence ofBordetella pertussis (B. pertussis). In this particularstudy, human MOG appeared to be more efficient than ratMOG in terms of the incidence of EAE. It is possible thatthe greater immunogenicity of human MOG in Lewisrats was linked to different epitopes outside the Ig-likeextracellular domain. Amino acid sequence comparisonindicates that there are more substitutions between hu-man and rat in the transmembrane domains of MOG(Fig. 1). However, the C-terminal moiety of MOG (aa121–218) has not been separately shown to have enceph-alitogenic potential. All other studies indicate that rMOG(the Ig-like domain of MOG) suffices in most cases forreproducible induction of EAE in mice, rats, and nonhu-man primates and that human and rat rMOG are equiv-alent in potency (Table II). One exception concerns theSJL mouse, which is reportedly highly susceptible torecombinant human rMOG (aa 1–120, produced in insectcells) (64), and not to recombinant rat rMOG (aa 1–125,produced inE. coli) (65). The latter studies both reportedthat this mouse strain develops severe EAE when immu-nized with the immunodominant peptide MOG peptide92–106, which contains only one substitution betweenhuman (F96) and rat (Y96). Therefore, it is unlikely thatthe differences in susceptibility to EAE are explained bythe different amino acid sequences. On the other hand,these findings possibly suggest that glycosylation of theIg-like domain of MOG, and/or solubility of the antigen,may be important for encephalitogenicity in the SJLmouse (64).

To summarize these observations, it appears that mostspecies and strains studied develop moderate to severe

Table I. Properties of the MOG Antigen

Ref. Nos.

Integral membrane protein specific to CNS myelin 20, 22, 39, 102Located on the outermost lamellae of the myelin sheath and on the surface of oligodendrocytes 46, 47, 59, 60Surface marker of oligodendrocyte maturation 54, 55Expression parallels myelination 52, 53Quantitatively minor component of myelinMolecular size of 26–28 kD on SDS-PAGE and tendency to form dimers 21, 22, 60, 102, 103Glycosylated in native form. N-linked glycosylation at asp 31 39, 48, 60, 102Highly conserved among mouse, rat, guinea pig, bovine, marsupial, and human, but absent in

avian and reptiles brains 37–40, 42, 104Maps to the MHC region in the mouse, rat, and human 36, 43, 44Alternative mRNA splicing variants in humans, not mice 104, 105Nonglycosylated extracellular domain produces CNS demyelinating disease in guinea pigs,

mice, rats, and primates See this review

AUTOIMMUNITY TO MOG 157


Tab

leII.

Enc

epha

litog

enic

Pro

pert

ies

ofN

ativ

eor

Rec

ombi

nant

MO

G(r

MO

G)

inV

ario

usS

trai

nsan

dS

peci

es,

and

Clin

ical

and

Pat

holo

gica

lPhe

noty

pes

a

Spe

cies

MH

Ccl

ass

IIre

stric

tion

elem

ent

Str

ain

Ant

igen

No.

ofim

mun

izat

ions

PT

Inci

denc

eof

EA

EC

linic

alco

urse

Rel

apse

sa

-MO

GA

bsD

emye

linat

ion

Ref

.N

o.

Mou

seH

-2gS

JL/J

Hum

anrM

OG

(1–1

20)

b1

115

/15

Chr

onic

,se

vere

No

1Y

es64

SJL

Rat

rMO

G(1

–125

)c2

11/

5A

cute

,m

ildN

DN

o65

H-2

dq

1B

iozz

iAB

/HR

atrM

OG

(1–1

25)c

21

5/6

Acu

te,

mod

erat

eN

oN

DN

o65

H-2

bC

57/B

L/6

Hum

anrM

OG

(1–1

21)

c1

16/

7C

hron

ic,

seve

reN

o1

Yes

106

H-2

bC

57/B

L/6

Rat

rMO

G(1

–122

)c1

14/

4C

hron

ic,

seve

reN

o1

Yes

79H

-2b

,p,q

C57

/BL/

10R

atrM

OG

(1–1

25)

c1

110

0%C

hron

icN

oN

DN

D10

7H

-2q

DB

A/l

Rat

rMO

G(1

–125

)c1

1/2

5/5

Chr

onic

,se

vere

No

1Y

es10

7H

-2g

7N

OD

/Lt

Rat

rMO

G(1

–122

)c1

14/

4C

hron

ic,

seve

reY

es1

Yes

79H

-2g

7N

OD

/Lt

Hum

anrM

OG

(1–1

21)c

11

9/9

Chr

onic

,se

vere

Yes

1Y

es10

6

Rat

RT

-1l

Lew

isR

atM

OG

(1–2

18)d

12

3/8

Chr

onic

,se

vere

Yes

1Y

es63

Hum

anM

OG

(1–2

18)d

12

10/1

0C

hron

ic,

seve

reY

es1

Yes

63R

atrM

OG

(1–1

25)c

12

9/11

Acu

te,

mod

erat

eY

es1

Yes

82R

T-1

nB

row

n-N

orw

ayR

atrM

OG

(1–1

25)

c1

27/

7A

cute

,le

thal

No

1Y

es67

Mar

mos

etO

utbr

edC

.ja

cch

us

Rat

rMO

G(1

–125

)c1

110

0%A

cute

,m

oder

ate

tose

vere

and

chro

nic/

rela

psin

g

1Y

es30

,66

,70

,71

,10

8

Rat

rMO

G(1

–125

)c1

23/

3A

cute

,se

vere

1Y

esun

publ

ishe

dH

uman

rMO

G(1

–125

)c1

23/

3C

hron

ic,

seve

reN

o1

Yes

72

Mac

aque

rhes

usO

utbr

edM

.m

ula

tta

Hum

anrM

OG

(1–1

25)c

11

8/8

Hyp

erac

ute,

fulm

inan

tN

o1

Yes

74

aW

here

avai

labl

eth

epr

esen

ceof

ahu

mor

alre

spon

seis

indi

cate

d.P

T,

B.

pert

ussi

s;N

D,

not

done

.bB

acul

oviru

sex

pres

sion

syst

emin

inse

ctce

lls;

glyc

osyl

ated

reco

mbi

nant

prot

ein.

c Exp

ress

edinE

.co

li;no

ngly

cosy

late

dpr

otei

n.dN

ativ

epr

otei

npu

rified

from

brai

ntis

sue.



EAE after immunization with the whole MOG moleculeor its extracellular domain. Where reported, EAE waspathologically characterized by significant demyelina-tion associated with perivascular infiltrates, with theexception of mice baring the H-2s (SJL) and H-2dq1

(Biozzi AB/H) MHC class II restriction haplotypes.Demyelination appeared to be associated with the pres-ence of autoantibodies to rMOG, especially in rats andprimates, where amplification of these antibody re-sponses resulted in hyperacute, lethal forms of EAE (66,67). The different origins of the MOG antigen did notresult in major alterations of the clinical or neuropatho-logical characteristics of EAE. Rather, the differences inthe incidence of disease and severity reported in thesestudies could be due largely to additional factors, such asvariations in housing environment, dose of antigen,adjuvants (presence or absence ofB. pertussis), and routeof immunization. In support of this hypothesis, a system-atic study of EAE conducted with nonglycosylated ratrMOG (aa 1–125) demonstrated that significant variationin EAE phenotype and lesion distribution could beobserved in a single rat strain, depending on the adjuvantregimen and physicochemical state of the rMOG em-ployed for immunization (68).

SPECIFICITIES OF PRIMARY T CELL AND B CELLRESPONSES IN rMOG-INDUCED EAE

Several studies have analyzed the fine specificity of Tcell and antibody responses using linear peptides over-lapping the sequence of the Ig-like domain of MOG in

animals actively immunized with rMOG. These data aresummarized in Fig. 2. Immune responses to the C-terminus portion of MOG, if any, have not been reportedto date.

Rodents

In inbred rodents, three major regions were identifiedas immunodominant for T cell responses. These includean N-terminus peptide (SJL mouse and Lewis rat), apeptide located within MOG aa 35–55 (CH3.SW,C57BL/6, NOD/Lt, Lewis rat), and one or more epitopeswithin the C-terminus portion of rMOG (SJL, C57BL/6,and NOD/Lt). It is clear that in most strains, the primaryT cell response is restricted to only one of these epitopes.This is also apparent when examining the encephalito-genic potential of individual peptides (as assessed byability to induce EAE by active immunization with shortpeptides or adoptive transfer of T cell lines), whichshows that a given strain generally responds only to asingle MOG peptide (see below). The specificity ofantibody responses has also been explored using linearpeptides of MOG and seems to correspond to the mainepitopes targeted by T cells.

Nonhuman Primates

In contrast to inbred rodents, immune responses toMOG appear to be more diverse in both New World andOld World outbred primates (C. jacchusmarmosets and

Fig. 1. Comparative deduced amino acid sequences of rat and human MOG. MOG shows a high degree of conservation between species, with mostsubstitutions located within the transmembrane domain. However, several substitutions located within the Ig-like, extracellular domain involveimmunodominant epitopes (see text). Shaded in gray are substitutions and boxed are transmembrane domains.



M. mulatta). The C. jacchusmarmoset (common mar-moset) is a New World primate that is highly susceptibleto immunization with whole myelin in adjuvant, whichresults in a chronic form of EAE with clinical andneuropathological characteristics that recapitulate thehallmark features of human MS (69, 70). In this species,sensitization with rat rMOG aa 1–120, and not MBP orPLP, results in chronic relapsing-remitting or severe

progressive forms of EAE with prominent demyelinationequivalent to that observed after immunization withwhole myelin (30, 70). Examination of primary T cellresponses inC. jacchus marmosets immunized withrMOG has revealed several epitopes, respectively, lo-cated between MOG aa 21–40, MOG aa 51–90, andwithin the C-terminus portion (Fig. 2). Fine epitopemapping of two of these encephalitogenic regions has

Fig. 2.Mapping of T cell and B cell epitopes in animals immunized with rMOG (human or rat). T cell epitopes (blue bars) were obtained at euthanasiaeither from lymphoid tissues (all species) or from PBMC (marmoset) by measuring proliferative responses to panels of overlapping peptides of rMOG.Epitopes of the humoral response against rMOG (red bars) were obtained by testing sera from immunized animals for the presence of Abs againstindividual peptides by ELISA. Arrowheads mark the positions of amino acid substitutions between rat and human rMOG (see Fig. 1). Asterisksdesignate peptide epitopes that were subsequently demonstrated to be encephalotiogenic.



identified MOG aa 28–36 and MOG aa 63–72 as the coreT cell epitopes, the sequence of which is totally con-served among rat, human, and marmoset (71) (unpub-lished data). A separate study has identified MOG aa24–36 as a major T cell epitope of MOG in marmosetsimmunized with human rMOG. Interestingly, thisepitope of MOG could be presented to T cells by amonomorphic MHC class II molecule that is peculiar tothis species (72, 73). In rhesus monkeys (M. mulatta)immunized with human rMOG, T cell responses werefound to be directed against several epitopes encom-passed within MOG aa 4–20, MOG aa 34–56, and MOGaa 94–116 (74). Although two of these epitopes (MOGaa 4–20 and MOG aa 34–56) have been proposed asimmunodominant for T cell responses in patients withMS (75), this has not been confirmed by additionalstudies (33). Collectively, these data indicate that T cellautoimmunity to MOG encompasses a broadly heteroge-neous repertoire in outbred populations.

Similar to rodents, mapping studies with linear pep-tides of rMOG in primates indicate that humoral re-sponses generally recognize amino acid sequences thatcorrespond to those of T cell epitopes (Fig. 2). Inmarmosets, however, analysis of fine specificities for theantibody response has identified two additional regionsof rMOG which so far have not been recognized as T cellreactive, e.g., aa 13–21 and aa 40–45. As is discussedlater, although these observations indicate that multipleregions of the protein may be targeted by autoantibodyresponses, they provide little information on the exis-tence of conformational antibody epitopes of MOG.

ENCEPHALITOGENIC POTENTIAL OFMOG-DERIVED PEPTIDES

The ability of synthetic peptides derived from theamino acid sequence of MOG to induce EAE by activeimmunization with adjuvant has been tested in manyspecies. Results are summarized in Table III.

Rodents

In most inbred strains, the immunodominant enceph-alitogenic epitope identified in rMOG-immunized ani-mals was necessary and sufficient in order to induce EAE(see also Fig. 2). For example, MOG aa 35–55 or its coreepitope was found encephalitogenic in H-2b (C57BL/6,C3H.SW, and C57L), H-2u (PL/J), and H-2g7 (NOD/Lt)mice (76–79). This peptide was also found to be themajor encephalitogenic region of MOG in the Lewis rat,in association with the RT11 class II restriction element(63, 80). In contrast, the encephalitogenic peptides in

H-2s (SJL/J and A.SW) and H-2q (DBA/1) mice arelocated within the C-terminus moiety, corresponding,respectively, to aa 92–106 and aa 79–96 (65, 81). Inaddition to immunodominant epitopes, additional pep-tides of the N terminus of MOG were found to inducesubclinical EAE in the Lewis rat (82). The repertoire ofencephalitogenic MOG peptides appears somewhat morediverse in the Biozzi AB/H mouse, where severalepitopes including MOG aa 1–15, aa 8–22, aa 43–57,and aa 134–148 (outside the Ig-like domain) have beenshown to produce EAE, although disease incidence wasnot predictable (65). These results confirm a strongassociation between MHC haplotypes and selective en-cephalitogenic regions of MOG in mice, with MOG aa35–55 clearly being immunodominant in several differ-ent strains.

In contrast to extensive investigations of T cell recep-tor (TCR) usage in MBP- or PLP-induced EAE, little isknown of the TCR Vb gene usage of MOG peptide-specific T cells. Mendelet al. (76, 77) have reporteddiverse TCR Vb gene usage by MOG aa 35–55-specificT cells derived from H-2b mice. The encephalitogenicMOG aa 35–55-reactive T cell lines expressed Vb1,Vb6, Vb8, Vb14, and Vb15 gene segments in C57BL/6and Vb1, Vb2, Vb6, Vb8, Vb10, Vb14, and Vb15 genesegments in C3H.SW. A predominant expression of TCRVb8.2 (40–48%) is observed in both strains. However,the C57L mouse bares the H-2b haplotype and has adeletion of Vb8 genes, is equally susceptible to MOG aa35–55, and, compared to the C3H.SW mouse, does notshow major alterations in TCR Vb gene usage (Vb1,Vb2, Vb6, Vb14, and Vb16) (77). These studies suggestthat the encephalitogenic response to MOG in H-2b mice,although restricted in epitope recognition, is diverse atthe level of TCR utilization.

The clinical course of EAE induced with peptideepitopes of MOG was variable, depending on the strainstudied. MOG aa 35–55-induced chronic progressive,nonremitting EAE in C57BL/6, C3H.SW, and C57Lmice, and clinical signs were highly reproducible fromanimal to animal (76, 77). In PL/J mice, clinical mani-festations of EAE appeared unpredictable, of delayedonset, and often started abruptly with severe impairment(78). Although the factors underlying such differencesare unclear, one explanation may be that the coreencephalitogenic epitope in PL/J (H-2u) mice is differentfrom that in H-2b mice. MOG aa 40–55 is stronglyencephalitogenic in mice, and MOG aa 35–55-reactive Tcell lines restricted by H-2b react with MOG aa 40–55but not with MOG aa 36–45 (76). The core encephali-togenic T cell epitope in H-2b mice appears to be MOGaa 40–48 (77). In PL/J mice, MOG aa 35–55-reactive T



Tab

leIII

.E

ncep

halit

ogen

icE

pito

pes

ofM

OG

inV

ario

usS

trai

nsan

dS

peci

esa

Spe

cies

MH

Ccl

ass

IIre

stric

tion

elem

ent

Str

ain

Ant

igen

No.

ofim

mun

izat

ions

PT

Inci

denc

eof

EA

EC

linic

alco

urse

Rel

apse

sa

-MO

GA

bsa

-pep

tide

Abs

Dem

yelin

atio

nR

ef.

Mou

seH

-2sS

JLaa

92–1

06b2

114

/16

Acu

te,

seve

reY

esN

DN

DY

es65

H-2

sS

JL/J

aa92

–106

12

15/1

7C

hron

ic,

seve

reY

esN

D92

–106

(1

)M

ild81

00

aa92

–106

11

12/1

3C

hron

ic,

seve

reY

esN

D92

–106

(1

)M

ild0

H-2

sA

.SW

aa92

–106

12

14/1

4C

hron

ic,

seve

reN

oN

D92

–106

Yes

00

0aa

92–1

061

18/

8C

hron

ic,

seve

reY

es,

with

prog

essi

onN

D92

–106

(1)

Yes

0

H-2

dq

lB

iozz

iAB

/Haa

1–15

c2

12/

11A

cute

,m

oder

ate

No

ND

ND

No

650

0aa

8–2

22

14/

6A

cute

,m

oder

ate

No

ND

ND

No

00

0aa

43–5

72

11/

5S

ever

eN

oN

DN

DN

o0

00

aa13

4–1

482

11/

5A

cute

,m

ildN

oN

DN

DN

o0

H-2

bC

57/B

L/6

aa35

–55

11

11/1

3C

hron

ic,

seve

reN

o1

35–5

5Y

es79

,10

90

0aa

35–5

51

14/

5-5/

5C

hron

ic,

seve

reN

oN

DN

DY

es76

00

aa40

–55

21

4/4

Chr

onic

,m

oder

ate

No

ND

ND

ND

00

0aa

1–21

,10

4–1

172

10/

?N

oE

AE

NA

ND

ND

ND

0H

-2b

C3H

.SW

aa35

–55

21

34/5

5C

hron

ic,

seve

reN

oN

DN

D?

00

0aa

40–5

52

14/

4C

hron

ic,

seve

reN

oN

DN

DN

D0

00

aa40

–48

21

4/5

Chr

onic

,se

vere

No

ND

ND

ND

77H

-2b

C57

Laa

40–

482

12/

6C

hron

ic,

mod

erat

eN

oN

DN

DN

D0

H-2

qD

BA

/1aa

73–9

0d1

12/

8C

hron

ic,

mild

No

ND

1(n

otsh

own)

ND

107

00

aa79

–90

11

3/5

Chr

onic

,m

ildN

oN

D1

(not

show

n)N

D0

00

aa79

–96

11

/212

/13

Chr

onic

,m

oder

ate

No

ND

1(n

otsh

own)

Mild

0aa

85–1

021

11/

6M

ildN

oN

D1

(not

show

n)N

D0

H-2

g7

NO

D/L

taa

35–5

51

111

/11

Chr

onic

,se

vere

Yes

135

–55,

92–1

06Y

es79

H-2

uP

L/J

aa35

–55e

32

3/13

Chr

onic

Yes

ND

ND

Mild

78aa

35–5

53

19/

14C

hron

icY

esN

DN

DM

ild0

Rat

RT

-1l

Lew

isaa

1–20

1–2

20/

4S

ubcl

inic

alN

/A1

1–20

,9

–25

No

820

0aa

9–2

51–

22

0/4

Sub

clin

ical

N/A

11–

20,

9–2

5N

o0

00

aa35

–55

12

14/1

8C

hron

ic,

seve

reY

es1

35–5

5Y

es63

00

aa35

–55

12

21/2

5M

ild–s

ever

eY

es1

37–

46,

43–5

0Y

es;

not

show

n80

00

aa35

–55

1–2

20/

4S

ubcl

inic

alN

/A1

35–5

5N

o82

Mar

mos

etou

tbre

dC

.ja

cch

us

aa21

–40

11

2/2

Chr

onic

,m

ildN

o1

21–

40,

31–5

0M

ildT

his

revi

ew0

0aa

1–20

,11

–30,

21–

401

12/

2C

hron

ic,

mild

No

11–

20,

11–3

0,21

–40

,31

–50

00

00

aa51

–70,

61–

80,

71–9

01

11/

1C

hron

ic,

mild

No

(2)

—0

00

0aa

81–1

00,

91–1

10,

101–

120

11

1/1

Chr

onic

,m

ildN

o1

91–1

10,

101–

120

00

00

Ove

rlapp

ing

20m

erpe

ptid

es1–

120

11

2/2

Chr

onic

,m

ildN

o1

1–20

,(1

1–30

),21

–40

,31

–50,

101–

120

00

aE

ncep

halit

ogen

icity

was

asse

ssed

byon

eor

mor

eim

mun

izat

ions

inth

epr

esen

ceor

abse

nce

ofB

.p

ert

uss

is(P

T).

Whe

reav

aila

ble,

info

rmat

ion

onan

tibod

ies

agai

nst

rMO

G(

a-r

MO

GA

bs),

MO

Gpe

ptid

es(a-p

eptid

eA

bs),

and

dem

yelin

atio

nis

incl

uded

.N

D,

not

done

;N

/A,

not

appl

icab

le.

bP

eptid

esal

sote

sted

but

not

foun

dto

indu

ceE

AE

incl

ude

over

lapp

ing

15m

erpe

ptid

esra

ngin

gfr

omaa

1to

92an

daa

106

to21

8.c P

eptid

esal

sote

sted

but

not

foun

dto

indu

ceE

AE

incl

ude

over

lapp

ing

15m

erpe

ptid

esra

ngin

gfr

omaa

15to

50,

aa50

to14

1,an

daa

141

to21

8.dP

eptid

esal

sote

sted

but

not

foun

dto

indu

ceE

AE

incl

ude

pept

ides

rang

ing

from

aa1

to84

and

aa91

to10

8.e P

eptid

esal

sote

sted

but

not

foun

dto

indu

ceE

AE

incl

ude

pept

ides

aa1–

21,

aa67

–87

,an

daa

202–

218.



cell lines react with MOG aa 36–45 but not with MOGaa 40–55 (78). This suggests that different epitopesencrypted within MOG aa 35–55 may influence diseasephenotype in these mouse strains. The influence of MHCgenes on EAE phenotype extends beyond the control ofT cell responses and may also determine the develop-ment and the magnitude of antibody responses as dis-cussed further below.

Nonhuman Primates

Data from our laboratory indicate that multiple peptideepitopes of MOG are encephalitogenic inC. jacchusmarmosets (Table III). Active immunizations with 100mg of MOG aa 21–40 (which contains a major T cellepitope), alone or in combination with equal amounts ofaa 1–20 and 11–30, reproducibly induced mild, chronicEAE. Neuropathologically, rare (1–3) inflammatory in-filtrates were observed, accompanied by moderate, albeitsignificant demyelination (Genainet al., in preparation).This syndrome could also be produced by immunizationwith a combination of peptides spanning residues aa51–90 and aa 81–120. Immunization with 100mg each of11 overlapping peptides corresponding to the entiresequence of human rMOG (aa 1–120) tended to producelesions that were more destructive than with immuniza-tion with individual groups of peptides but remainedscarce and mostly confined to the cervical spinal cord.No peptide or combination of peptides was capable ofreproducing the protracted, multifocal lesions associatedwith prominent demyelination that result from immuni-zation with whole rMOG in this species.

ANTIBODY RESPONSES IN MOGPEPTIDE-INDUCED EAE

Rodents

Immunization with rMOG and its peptide MOG35-55leads to demyelinating forms of EAE in C57BL/6 (H-2b)and NOD/Lt (H-2g7) mice. Antibody responses in thesemodels were found to be directed against whole rMOGas well an epitope located within MOG aa 35–55. Inaddition, epitope spreading can be observed in NOD/Ltmice which develop an antibody response against MOGaa 92–106 after immunization with aa 35–55 (79). Inboth A.SW and SJL mice (H-2s), immunization againstMOG aa 92–106 leads to a demyelinating form of EAEwith a humoral response directed against MOG aa92–106, however, the presence of antibodies against theentire extracellular domain of MOG has not been as-

sessed (81). Other studies of mouse susceptibility toimmunization against MOG peptides (H-2dq1, H-2b,p,q,H-2q, and H-2u) have not focused on analytical descrip-tion of antibody responses against either rMOG orMOG-derived peptides.

In Lewis rats, s.c. immunization with rMOG in thehind foot pad induced an acute, moderate form ofdemyelinating EAE with humoral responses directedagainst rMOG, MOG aa 1–20, MOG aa 9–25, and MOGaa 35–55. Animals immunized with MOG aa 1–20 orMOG aa 35–55 developed antibody responses directedagainst rMOG and the sensitizing antigen, without evi-dence of epitope spreading (82).

Nonhuman Primates

Immunization ofC. jacchusmarmosets with rMOGinvariably leads to a demyelinating form of EAE, with ahumoral immune response directed against severalepitopes contained within MOG1-50 and 51–80 (see Fig.2). Analysis of serum reactivity in animals immunizedwith single or groups of individual peptides revealed thatantibodies developed in these animals with specificity forthe sensitizing antigen, without evidence of epitopespreading. One exception was observed with the group ofpeptides corresponding to MOG aa 51–90, which did notgive rise to significant antibody responses. Immunizationof marmosets with the 11 overlapping 20mer peptidesspanning the entire sequence of the extracellular domainof MOG, induced antibody responses that were directedat epitopes within MOG1-50 and MOG101–120 (TableIII). It is noteworthy that humoral reactivity to peptidescontaining MOG aa 63–72 could be detected only inanimals immunized with rMOG, and not in animalsimmunized with any combination of the overlappinglinear peptides. The latter observation may indicate thatMOG aa 63–72-specific T cells are not able to providesufficient B cell helper function or that development ofan antibody response against this domain of MOG isdependent upon the recognition of conformationalepitopes present only in rMOG.

RESPECTIVE PATHOGENIC ROLES OF T CELL ANDANTIBODY RESPONSES TO MOG

The respective roles of T cell and antibody responsesin EAE pathogenesis can be studied using adoptive T celltransfer and/or passive antibody transfer systems withsingle or multiple antigens. Adoptive transfer experi-ments involving MOG-specific T cells have been per-formed in several species (Table IV). The results of theseexperiments are discussed in context of observations in



actively immunized animals and differ between strainsand species.

Rodents

Adoptive transfer of MOG aa 35–55-specific T cellsresulted in clinical EAE in H-2b (C57BL/6 and C3H.SW)mice and H-2g7 (NOD/Lt) mice, as did active immuni-zation with this peptide (76, 77, 79). Histologically,inflammatory foci could be seen throughout the CNS inC57BL/6 mice, but the presence of demyelination wasnot assessed (76). In PL/J mice, transfer of lymph nodeor spleen cells derived from animals sensitized withMOG aa 35–55 failed to induce clinical disease but wasable to produce CNS inflammation, and not demyelina-tion (78). Adoptive transfer experiments have not beenreported for other MOG-susceptible mouse strains, in-cluding Biozzi AB/H (H-2dql), C57/BL/1 (H-2b,p,q)DBA/1 (H-2q), and SJL (H-2s). Although adoptivelytransferred mice of the PL/J (H-2u) strain were observedfor only a short period of time (2 weeks), the discrepancybetween clinical EAE and neuropathology is reminiscentof adoptively transferred EAE in rats. In both Lewis andBrown Norway rats, adoptive transfer of MOG-specificor aa 35–55-reactive spleen cells or T cell lines failed toinduce significant neurological impairment (23, 63, 67,82, 83) but resulted in severe inflammation with promi-nent perivascular cuffing (23, 82, 83). These experi-ments, together with the occurence of EAE after activeimmunization with MOG peptides, unequivocally dem-onstrate a pathogenic role for MOG-specific T cells inCNS inflammation. However, the severity of EAE and

neuropathological phenotypes appear dependent on thestrain and the sensitizing antigen, especially with regardto the presence of primary demyelination.

What variables determine the severity of the inflam-matory response against MOG in rodents and the inci-dence of demyelination or irreversible CNS tissue de-struction? As outlined earlier, MHC class II genes playan important role in restricting encephalitogenic epitopespresented to T cells, which may have different disease-inducing potential (Table III). However, the variableEAE phenotypes observed in the different strains mayalso be linked to additional factors. In two mouse strainsbaring H-2s (SJL/J and A.SW), MOG aa 92–106 caninduce either chronic, relapsing–remitting EAE (SJL/Jmice) or nonremitting EAE (A.SW mice) (81). Thedifferent responses of SJL/J mice and A.SW mice toimmunization with the same MOG peptide suggest thatgenes outside of the MHC region contribute to thephenotype of EAE. Non-MHC genes can influenceclinical disease, T cell functions such as the secretion ofIFN-g (84), or other mediators contributing to CNSinflammation and/or demyelination. Of particular impor-tance in determining the course of EAE are the timing ofcytokine release in relationship to inflammatory events inthe CNS (85) and the presence and pathogenicity ofMOG-specific antibody responses.

We have examined correlations among clinical signsof EAE, the presence of MOG- and MOG peptide-specific antibodies, and demyelination reported in studiesof rodent EAE. In EAE actively induced by immuniza-tion with MOG or rMOG, it is clear that severe clinicalEAE and demyelination is consistently associated with

Table IV. Adoptive Transfer of MOG-Specific T Cells in Various Strains and Speciesa

SpeciesMHC class II

restriction element StrainImmunzing

antigenMethod ofinduction Clinical disease Inflammation Demyelination

Ref.No.(s.)

Mouse H-2u PL/J aa35–55 Lymph node orspleen cells

No Yes ND 78

H-2b C57/BL/6 aa35–55 T cell lines Yes (chronic) Yes ND 76H-2b C3H.SW aa35–55 T cell lines Yes (chronic) ND ND 77H-2g7 NOD/Lt aa35–55 Spleen cells Yes (chronic) ND ND 79

Rat RT-11 Lewis Rat MOG(1–218)

Spleen cells No ND ND 63

RT-11 Lewis a35–55 T cell lines No Yes No 23RT-11 Lewis aa1–20 T cell blasts No (weight loss) Minimal No

aa35–55 T cell blasts Yes (mild) Yes No 82,83aa60–67 T cell blasts No No No

RT-1n Brown-Norway Rat rMOG,(1–125,E. coli)

T cell blasts No Yes ND 67

Marmoset Outbred C. jacchus None (naive) T cell lines(aa21–40)

Yes (acute,monophasic)

Yes Minimal 95

aSummarized are adoptive transfer experiments reported in mice, rats, and marmosets, with the resulting clinical and pathological phenotypes.Prominent demyelination is not typically present in MOG adoptive transfer EAE. ND, not done.



the presence of serum MOG-specific antibodies (TableII). This is consistent with observations that passivetransfer of antibodies specific for whole MOG worsensthe course of MBP-induced EAE and induces demyeli-nation in SJL mice (86) and that EAE is also aggravatedin a mouse engineered to carry a transgene encoding fora monoclonal antibody against MOG (87). The associa-tion between demyelination and the humoral responses isless straightforward in the case of EAE induced withMOG peptides. Accounts of detailed neuropathologicalanalysis are given only for C57BL/6 (H-2b), NOD/Lt(H-2g7), SJL (H-2s), PL/J (H-2u) mice, and Lewis (RT-1l)rats (Table III). C57BL/6 and NOD/Lt mice developsevere chronic EAE after immunization with MOG aa35–55, in association with rMOG- and MOG aa 35–55-specific antibodies and neuropathologically, show demy-elination (79). SJL and A.SW mice, which respondexclusively to MOG aa 92–106, also develop chronicEAE with demyelination (65, 81), in association withanti-MOG aa 92–106 antibodies (81). One differencebetween these mouse strains is that the NOD, SJL, andA.SW develop relapses, in contrast to the B6 mouse.PL/J mice develop chronic relapsing EAE after immuni-zation with MOG aa 35–55 and display moderate demy-elination. Demyelination was not observed after adoptivetransfer of MOG aa 35–55-reactive T cells in this strain(78). This suggests that antibody responses to peptidescould play a role in the induction of demyelination,although antibody responses were not assessed in theactively immunized PL/J mice.

Thus, although these observations of mouse EAEindicate that development of antibody responses thattarget certain epitopes of MOG may influence clinicaland pathological phenotypes of MOG-induced EAE inmice, they fail to demonstrate a specific role of antibod-ies in promoting demyelination in all strains. A recentstudy has demonstrated that immunization of C57BL/6,B cell-deficient mice with MOG aa 35–55 is sufficient forthe development of severe clinical disease and CNSdemyelination that are comparable to those observed inwild-type animals (88). Unfortunately, the presence of

demyelination has not been assessed in this strain afteradoptive transfer of MOG aa 35–55-reactive T cells (76),thus it is not possible to understand to what extentantibodies specific for this peptide may contribute toEAE pathology. An additional important observation inthe C57BL/6 B-less mouse is that, while these animalsare fully susceptible to immunization with MOG aa35–55, they fail to develop clinical EAE and demyelina-tion if immunized with whole rMOG (Table V) (89).These findings have several possible explanations: thefirst is that, indeed, MOG-specific autoantibodies canproduce demyelination and worsen EAE in mice, butpathogenicity for these antibodies is linked to theirability to recognize conformational epitopes of MOG,and not linear determinants; second, this suggests that, inaddition to immunoglobulin production, B cells mayhave other important functions for the full developmentof EAE, including antigen processing and presentation.In the case of other strains such as Biozzi AB/H,insufficient information is available to understandwhether these mice fail to mount a pathogenic antibodyresponse to explain the absence of demyelination. Itwould be of interest to explore further the variouspathogenic mechanisms of MOG-induced EAE in mice,for example, by passive antibody transfer experimentsand/or cross-breeding of these strains with soluble im-munoglobulin-deficient mice, which retain expression ofthe B cell surface receptors (90).

In contrast to mice, a synergism between encephalito-genic T cells and pathogenic antibody is clearly involvedin the pathogenesis of demyelinating EAE in rats. InLewis rats, inflammation mediated by MOG-specific Tcells fails to induce gross neurological deficits anddemyelination (23, 63, 82, 83). Although Adelmanet al.were unable to induce severe and demyelinating EAEusing MOG aa 35–55 (82), in all other investigationsactive immunization with either whole MOG or MOG aa35–55 produce demyelinating EAE associated with an-tibody responses restricted to the immunizing antigen(Tables II and III). The demyelinating phenotype andsevere clinical EAE can be restored in recipients of

Table V. Immunogenic Properties of rMOG and MOG aa 35–55 in C57/BL/6 (H-2b) B Cell-Deficient Mice

Strain AntigenNo. of

immunizations PTIncidenceof EAE Inflammation Demyelination

T cell responseto antigen Antibody Ref. No.

B2/2 aa35–55 2 Yes 10/10 Yes Yes ND 2 88WT aa35–55 2 Yes 5/5 Yes Yes ND Yes

(aa35–55)B2/2 rMOG 2 Yes 0/20 Minimal Minimal 1 2 89WT rMOG 2 Yes 18/20 Yes Yes 1 NDB2/2 aa35–55 2 Yes 12/19 Yes Yes ND 2 0WT aa35–55 2 Yes 7/15 Yes Yes ND ND 0

aB2/2, targeted disruption of the IgM H-chain; WT, wild type; PT,B. pertussistoxin; ND, not done.



adoptive T cell transfer, by cotransfer of MOG-specificantibodies (23). This result is consistent with previousexperience that anti-MOG antibodies also aggravateMBP-induced EAE in Lewis rats (27, 29). Furthermore,in Brown Norway rats, MOG induces an acute and lethalform of EAE, which is linked to increased production ofautoantibodies (67). These findings, and other studies ofgenetic susceptibility to EAE, indicate that, in addition toMHC class II, autoimmunity to MOG is under thecontrol of multiple other genes in rats (91, 92).

Nonhuman Primates

Because of their close phylogeny to humans and thesimilarity of EAE in this species to human MS, themarmoset model has been instrumental in elucidatingimmunopathological mechanisms involved in the devel-opment of demyelinating lesions. Adoptive transfer of Tcells is possible inC. jacchusmarmosets, due to a naturalbone marrow chimerism. It has been possible to demon-strate an obligatory role for antibodies to MOG in thissystem, using a combination of adoptive transfer ofMBP-reactive T cells (or active immunization withMBP) and purified anti-MOG antibodies (30, 70). Theimportance of antibodies in marmoset EAE is alsoemphasized by observations that immune deviation ofMOG-specific responses toward a Th2 phenotype ofcytokines resulted in hyperacute, lethal forms of EAE(66) and that animals immunized with MP4, a chimericprotein of MBP and PLP, develop severe EAE anddemyelination only in association with determinantspreading of their antibody response to MOG (98).

The role of MOG-specific T cells and antibodies wasfurther explored by passive transfer of T cell clonesspecific for MOG aa 21–40 between syngeneic marmo-set siblings (Table IV). Interestingly, these T cell clonescould be readily derived from the PBMC of healthy,unimmunized animals, a finding that parallels our previ-ous observation that MBP-specific T cell clones arepresent in the natural circulating repertoire of theseprimates (94). Adoptive transfer of MOG-reactive T cellclones resulted in mild, acute monophasic clinical EAE,and minimal demyelination, albeit significantly moreCNS disease was present compared to recipients ofMBP-reactive T cell clones (94, 95). The extent andseverity of disease were similar to that induced by activeimmunization with MOG peptides, however, the clinicalcourse of EAE was monphasic and not chronic. Thissuggests that MOG-reactive T cells are significantlymore pathogenic in primates than are MBP-reactive Tcells but are not able to induce sustained CNS inflam-

matory responses and/or permanent demyelination withgliosis, which appear to be dependent on antibodies.

Because of the prime importance of humoral re-sponses to MOG in promoting or increasing demyelina-tion and tissue destruction, it is of interest to identify theepitopes that are targeted by pathogenic populations ofautoantibodies. Antibody responses in marmosets immu-nized with MOG-derived peptides are specific for theimmunizing antigen, and no determinant spreading hasbeen recorded to date. These antibodies most often alsorecognize rMOG (with the exception of those directedagainst peptides contained within MOG aa 51–90), butthe actual determinants may differ from those for anti-bodies present in rMOG-immunized marmosets (Fig. 2).The marked differences in clinical and neuropathologicalfeatures between MOG peptide- and rMOG-immunizedanimals suggest that pathogenic antibody populations areselectively produced in rMOG-immunized marmosets.Because of their cross-reactive specificities, these differ-ent antibody populations cannot be easily distinguishedone from another in standard ELISA assays.

In an attempt to clarify the epitopes targeted bydemyelinating autoantibodies inC. jacchus, we haveexamined the molecular diversity of the MOG-specificantibody repertoire in rMOG-immunized animals using acombinatorial library of phage-displayed antibody frag-ments. This analysis is in progress but, indeed, showsthat antibodies with a very high affinity to rMOG, whichare capable of competing with the native serum antibod-ies produced by rMOG-immunized marmosets, recog-nize exclusively structural epitopes of MOG, and not thelinear peptides (96) (von Bu¨dingenet al., in preparation).These data provide evidence that several populations ofantibodies with different pathogenic potential coexist inmarmoset EAE and that demyelinating antibody popula-tions could be directed against conformational epitopesof this protein. In support of this hypothesis, an obser-vation by Brehmet al. (97) has shown that a murinemonoclonal antibody which recognizes the linear epitopeMOG aa 1–26 fails to mediate demyelinationin vivo inrats, although this antibody is fully capable of recogniz-ing whole MOG. Further dissection of the specificities ofantibody responses to MOG and their pathogenic poten-tial will be of considerable interest, since it will helpdefine the targets for selective therapeutic interventionthat could prevent demyelination.

CONCLUDING REMARKS

The data summarized here highlight MOG as a uniqueCNS autoantigen. Although MOG is exposed at themyelin surface, expression has not been unequivocally



demonstrated outside the CNS, which implies that im-mune responses to this antigen may escape the control ofcentral thymic tolerance. It is clear that heightenedmemory responses to MOG exist in healthy individualsof outbred species (33, 95, 98, 99) (and Koehleret al., inpreparation), which have full capacity to induce CNSinflammatory disease as demonstrated by adoptive T celltransfer in the marmoset (95). These potentially autoag-gressive responses may arise early in life via mecha-nisms of mimicry to yet unknown self molecules, assuggested by the recent observation that receptor editingof MOG-specific immunoglobulins can take place in atransgenic mouse model that lacks the MOG gene (100).Mimicry to viral proteins has also been demonstrated forMOG, although this is not a feature unique to this antigen(101). The lack of spontaneous CNS-specific autoimmu-nity in most normal individuals implies the presence ofspecific regulatory mechanisms to maintain immunehomeostasis, which would be of interest to explore astargets for future therapeutic intervention.

Regardless of the mechanisms that give rise to andcontrol autoimmunity to MOG, the encephalitogenicproperties of this antigen probably lie within its abilityto induce immune responses that are highly patho-genic. Although some laboratory strains of mice ap-pear capable of developing CNS demyelination that ismediated by MOG-specific T cells, the role of auto-antibodies against MOG in tissue destruction has beenunequivocally demonstrated, especially in nonhumanprimates. Importantly, pathogenic antibody responsesagainst MOG have also been demonstratedin situ inMS brain (34). The identification of MOG and subse-quent studies of MOG-induced EAE have afforded thedemonstration that synergism between T cell andantibody responses to a single antigen of myelin canresult in CNS inflammatory lesions that recapitulatetypical lesions of MS. In addition, many experimentsreviewed here show that phenotypic expression ofautoimmunity to MOG may depend on specificitiesand molecular targets of the antibody response toMOG, rather than on factors controlled by cellularimmunity. This should stimulate further studies ofimmune responses to MOG, including the completecharacterization of structural epitopes targeted bypathogenic antibodies.

ACKNOWLEDGMENTS

This work was supported by grants from the NationalInstitutes of Health (AI 43073 to S.L.H.) and the Na-tional Multiple Sclerosis Society (JF2087-A-2 toC.P.G.). P.V. was a postdoctoral fellow of the Spanish

Ministry of Health (FIS 96/5122 and 97/5459). H.-C.v.B.is a postdoctoral fellow from the National Institutes ofHealth. N.T. is a postdoctoral fellow from the NationalMultiple Sclerosis Society. J.C.O. was a postdoctoralfellow from The Association pour la Recherche Contre laSclerose en Plaque and The Programme Lavoisier fromthe French Foreign Office.

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Immune Responses Against the Myelin/Oligodendrocyte Glycoprotein in Experimental Autoimmune Demyelination