- Email: [email protected]
Neurological diseases
Neurological diseases Hartmut
Wekerle
Max-Planck Institute for Psychiatry, Munich, Germany
Recent advances have improved our understanding of the T-cell recognition process in neuroimmunological autoimmune disease as well as the involvement of major histocompatibility complex molecules and cell adhesion molecules in the autoimmune attack.
Current Opinion in Immunology 1991, 3:896-901
Introduction
Autoantibodies
The number of neurological diseases in which an autoimmune pathogenesis is suspected is considerable. The number of disorders in which autoimmune mechanisms have been proven is much fewer. These autoimmune mechanisms may be identified by autoantibodies that bind to defined structures, and mediate disease following adoptive transfer.
Myasthenia
Central nervous system (CNS) autoimmunity in the absence of humoral autoantibodies is more diEcult to determine. In multiple sclerosis (MS), for example, autoimmunity has been suggested by histology, MHC-linked susceptibility and similarity to experimental autoimmune encephalomyelitis (EAR) models. Other diseases, such as narcolepsy, are suspected to have an autoimmune component solely because of their peculiar genetic control. Thus, the discovery of a large number of autoimmune diseases of the nervous system may be anticipated. Research Into autoimmunity within the nervous system is by no means restricted to neuroimmunology. A better understanding of cellular immunology and autoimmunology in general has also been gained. RAE models were the Iirst to allow the establishment of autoaggresslve T-lymphocyte lines, which may be used as probes to provide Invaluable Insights into epitope recognition, TCR gene usage, and T-cell-directed imrnunotherapies. This trend seems to be continuing, possibly with a certain shift of the main objectives. Although the T-cell recognition process was considered to be the most exciting feature of neuroimmunological autoimmune research, many workers now address other issues such as regulation of MHC expression in the target tissues and cell adhesion molecules Involved in the autoimmune attack. .-
in
neurological
diseases
gravis
Myasthenia gravis (MG) was the first, and still is the best characterized neurological disease resulting from pathogenic autoantibodies. It is undisputed that ‘spontaneously’ arising autoantibodies, many of which are directed against an epitope cluster, ‘main immunogenic region’ (ME), located within a circumspect sequence area of the acetylcholine receptor (AChR) a-chain [ 11, are responsible for the neurological defects that are typical of the disease. The stimulus for autoantibody production in MG is unknown. The very strict association of the disease with abnormalities in the thymus has suggested that the first step of autosensitization occurs within the thymus. Indeed, the prevailing MG-related thymus lesion, thymic hyperplasia, provides the key requirements for local T helper cell activation. It contains AChR-producing myoid cells, antigen-presenting interdigitating cells arranged in a particular spatial pattern [ 21, as well as a relatively high number of AChR autoreactive T cells (3-l. Intrathymic activation of AChR-speci6c T cells with subsequent helper effect on AChR-reactive B lymphocytes would account for these findings. Peptide epitopes have been mapped on a number of MG-derived anti-AChR T-cell clones [4*]. But AChR-specific T-cell clones are not at all speciiic for MG, although they can be isolated from the peripheral blood of healthy donors, and are, therefore, components of the normal T-cell repertoire [ 5.1. The role of neoplastic thymus changes in MG was obscure until recently. The group of Miiller-Hermelink [6**] first demonstrated serological cross-reactivity of thymoma epithelial membranes with anti-A&R monoclonal antibodies that were directed against cytoplasmic epitopes.
Abbreviations AebR-acetylcholine receptor; BBB-blood-brain barrier; CAM-cell adhesion molecule; CNS-central nervous system; PAP-experimental autoimmune encephalomyelitis; IL-interleukin; lEh4S-Lambert-Eaton myasthenic syndrome; MBP-myelin basic protein; MC-myasthenia gravis; MIR-main immunogenic region; MS-multiple sclerosis; NCF-nerve growth factor; PLP-proteolipid protein; PNS-peripheral nervous system; MS-stiff-man syndrome; TCR-T-cell receptor; TNF-tumor necrosis factor.
@ Current Biology Ltd ISSNO952-7915
Neurological
These *analyses indicated that the membrane antigen involved is not related to the AChR gene family, but that the cross-reaction reflects an unexpected case of molecular mimicry. It is possible that T cells which recognize the peptide sequence shared between thymoma protein and AChR may activate B cells, producing genuine anti-AChR autoantibodies in a second step.
lambert-Eaton
myasthenic syndrome
Thanks to the work of Newsom-Davis and colleagues [7=], the Iarnben-Eaton myasthenic syndrome (LEMS), a rare presynaptic disturbance of neuromuscular transmission has been characterized as a second example of autoantibody-mediated disease peripheral nervous system (PNS). These workers demonstrated the pathogenic effect of LEMS-derived autoantibodies in in vim transfers
[81. Recently, it has become clear that the molecular target of LEMS autoantibodies is the presynaptic calcium transport system and binding occurs to calcium channels in vitro [7*], and presumably in zlivo. In other neurological diseases, autoantibodies against CNS components have been demonstrated, without formal proof of their pathogenic character. In paraneoplastic cerebellar degeneration, for example, autoantibodies that bind to neuronal structures, e.g. Purkinje cells, have been found [9*]. The mechanism of action of these autoantibodies has not been determined. It is still unclear how the autoreactive immunoglobulins cross the bfood-brain barrier and, in addition, it is hard to explain how they can cross the target-cell membrane to reach the intracellular autoantigens. A most Intriguing case of putative autoimmune CNS disorder is ‘stiff-man syndrome’ (SMS). Autoantibodies against glutamyl decarboxylase, an enzyme involved in the metabolism of GABA, have been found in at least some patients with SMS. Interestingly, similar autoantibodies were demonstrated in patients with autoimmune diabetes mellitus, which may explain the occasional link between these disorders [lo**].
T cells in neurological diseases: MS as a paradigm In MS as is any cell-mediated human autoimmune disease, the definitive proof of the causal involvement of autoaggresive T lymphocytes would be made by transfer experiments which, for obvious reasons, are impossible to carry out. Thus, evidence for the autoimmune nature of MS is indirect and includes the characteristic histological features of the lesion, and the striking sUnilarity to some variants of an autoimmune model disease, EAE. More recently, one group found evidence for an increased frequency of somatic mutations in myelin basic protein @BP)-specific T-cell clones from MS patients, which was thought to reflect strong proliferation, as a consequence of an autoimmune reaction [ 1 l**] .
diseases
Wekerle 897
Several groups have isolated myelin-specific T lyrnphocytes to characterize the autoimmune pathogens of MHCrestricted recognition of myelin epitopes [12.-14’1 and their use of T-cell receptor (TCR) variable region genes [14.,15**,16*,17*]. These studies were inspired by work in rodent EAE, which established that the autoaggressive T-cell clones were directed against a very narrow spectrum of dominant target epitopes, and used a limited repertoire of T-cell receptor V region genes [ 18.1. Results from studies in humans have been unexpectedly disparate. Some groups have noted dominating epitopes in the carboxy-terminal part of MBP, others in the central part, whereas still others found codominance of these peptide sequences, or reactivity against multiple epitopes placed all along the MBP molecule [13*,18*]. Epitope mapping under highly defined conditions (use of human MHC transfectants as antigen-presented cells [13*,14*] will be required to define epitope preference in the human anti-MBP response. Clearly, however, there is no cogent evidence of an MBP epitope that is associated with T cells from MS patients speciEcaUy. In certain strains of rodents, encephalitogenic, MBP-specific T cells use very narrow repertoires of TCR genes, a finding that has given rise to novel TCR-targeted vaccination strategies (reviewed by Weiner et al. pp 936940). TCR dominance has been reported in MS plaque i<rates [ 19.1, which suggests that T cells inIiltrating MS brain tissue use a limited repertoire of TCR V genes. The specificity of these cells has not been determined, however. TCR analyses of myelin-specific human T-cell clones has revealed a more intricate pattern of gene usage. Expansion of MBP-specilic T-cells clones using identical V genes has been reported in several MS patients and in other cases, a broader spectrum of TCR gene usage has been seen [l@] (Giegerich et al, submitted for publication).
Activation of autoimmune T cells by autoantigens, molecular mimicry and superantigens Until very recently, most autoImmunologIsts were convinced that MBP was unique in eliciting a myelin-directed autolmmune attack within the CNS. Over t.ha past ?few years, however, other structures, particularly proteolipid protein (PLP), have been reported to be potential encephalitogens. Work carried out in the fifties by Waksman and Lees indicated that PIP might be a key encephalitogen, at least in some species or some individuals. Further evidence for this was provided by T-lymphocyte line transfers into the Lewis rat [20] and the SJL mous@[21], and through active Induction of EAE by synthetic PLP peptides [ 221. Recently, it was found that SJI/J mice Imtnunized with crude spinal cord homogenate have preferential activation and expansion of PLP rather than MBPspecUic T-cell clones [23m*] and mice tolerized against
898
Autoimmunity
PLP (but not against MBP) are resistant to RAE induction by spinal cord homogenate [ 241. There is evidence that in chronic relapsing RAR of the Fl(SJI./J x PI/J) hybrid mouse initial MBP-specific T-cell triggers may activate subsequent anti-PLP T-cell responses [25*]. Activation of autoimmune encephalitogenic T-cell clones, which are components of the intact rat [27] and human [9’,10**,27,28] immune system is a rare event considering the low incidence of spontaneous FXE and MS. As ptimary immunization of these clones by antigen presentation by CNS glia is not very likely, other peripheral mechanisms should be investigated as stimuli for the pathogenic T-cell responses. Molecular mimicry is one of these mechanisms. Fujlnami and Oldstone [29] were the lirst to provide evidence for viral peptides cross-activating MBP-specific, encephalitogenlc T-cell clones to trigger EAR. More recently, humoral autolmmune mimicry reactions were found to participate in the subacute vnriant of Theiler’s virus encephalitis [30..]. T-cell mimicry responses were also noted between uveitogenic peptides and viral [31-J sequences. An alternative method for activating pathogenic T-cell clones could involve microbial ‘superantigens’. Sakai et al [32] reported that encephalitogenic T-cell clones from SJL/J mice ‘co-recognized’ allogeneic Mls determinants [33*]. After the recent description by Ben-Nun [ 341 of interactions of staphylococcal enterotoxins (negative) with encephalitogenic T-cell clones the first demonstration of superantigen-triggered RAE is awaited with much interest.
Genetics
Much work has been devoted to identifying genetic factors predisposing to autoimmune susceptibility. In the case of neurological diseases, most of these studies have provided Interesting results, but are still far from identifying ‘the’ MS susceptibility gene. The three molecular components of the MBP/T-cell recognition complex have been screened for genetic polymorphisms that may be affiliated with MS. There is an MBP-gene polymorphism, which seems to be overrepresented ln MS patients [3+]. TCR gene polymorphisms were screened by several groups and restriction fragment length polymorphism RPLP studies indicated the occurrence of certain TCR allotypes ln some populations [35*]. Attempts to further investigate the MHC-related MS ‘disease gene(s)’ have been frustrating. Immunogenetics may be of more use in the illumination of the pathogenesis of narcolepsy. Narcolepsy, characterized by a profound disturbance of sleeping behavlour was surprisingly found to be associated with an HLA-DR2 haplotype- [36]. This finding led to a detailed scrutiny of the human HLA D region, which did not identify any abnormal genes [37]. Although there is no formal evidence of lmmunopathologlcal mechanisms in narcolepsy, its close association with DR2 haplotypes, and the recent demonstration of a linkage in canine narcolepsy [38*]
maintains interest in the search for (auto-) immune factors.
Cytokines
Because cytokines are essential in orchestrating the cellular autoimmune attack against autoantigens, much attention has been devoted to their study in autoimmune diseases and in models for these diseases. In MS, products of activated T cells such as IL-2, interferon (IFN)-)I, and ThFa (a mediator produced by T cells and macrophages) have been demonstrated [ 39*,40*,41**]. Furthermore, cytokines; such as IL-1 and IL-~ [42*,43*], which are produced by a variety of cells are found in increased amounts in CNP/PNS autoimmunity. Cytokine elevation is, however, also seen in other intlammatory disorders of the CNS. In addition to their role as mediators between (auto-) immune cells, cytokines may have functions that are specilic to the nervous system. Many cytokines directly bind to structures within the nervous system, and at least some of these are produced by local glia cells. The work of Fontana et all [44] first indicated that glia cells, and among them astrocytes and rnicroglia cells are efficient producers of cytokines including IL-1 [30]. There is evidence that at least some cytokines are involved in physiological linking of the CNS to the immune system. IL-l, for example, is known to have a profound impact on sleeping behaviour [45**]. Furthermore, the interplay of cytokines with nexve growth factors have been identified recently. Studies by Thoenen’s group have provided evidence for a more general function of cytokines and IL1 has a profound effect on regulation of nerve growth factor in the CNS [46**]. Macrophages are required to trigger the intact program of cellular regeneration in CNS and PNS 147.1, and cytokines secreted by these macrophages may be involved as mediators. Conversely, nerve growth factor seems to have effects on diverse immune cells and thus may modulate immune functions [48-l. This, however, remains to be analyzed in detail. TNF-a may have a function in effector mechanisms that lead to demyelination and gliosis [40*,49]. This contention is supported by a recent study that demonstrated a close association between the course of MS and TNFa levels in the CSF [41**]. the TNF-a gene is located within the human HIA gene complex and shows polymorphisms, which might be related to certain autolmmune disease [49]. How similar polymorphisms may control susceptibility to MS or other inflammatory diseases of the CNS remains to be elucidated.
Cell-adhesion
molecules
Research into cell-adhesion molecules (CAM S) is progressing rapidly. CAMS have crucial roles in the development and in the maintenance of the nervous system. They are involved ln directing guiding axonal growths proper
Neurological diseases Wekerle 899
association of glia cells between each other with neurons. In addition, CAMS mediate interactions with the immune cells that are required for entry into the CNS and their communication with CNS cells in immune surveillance and autoimmune disease (35.1. Particular attention has been paid to the expression of CAM in MS plaques [ 36.1, where they may be involved in autoantigen presentation and cellular effector mechanisms Another focus of CAM expression is the blood-brain barrier (BBB) [37-l. Here, inducible CAMS are of interest [38-l because they may be involved in guiding circulating immune and inflammatory cells into the CNS, and thus co-determining the fate of an intracerebral inflammation. Production of soluble inhibitors may be a promising novel strategy to interfere with BBB traffic in MS and other inflammatory brain disorders 139’1.
7. .
Lm K, IANG B, JOHNSTON
8.
FUKLJNAGA H, ENGEL AG, LANG B, NRYSOM-DAVIS
Papers of have been . of . . of 1.
2.
special interest, published within the annual period of review highlighted as: I interest outstanding interest
Tzr\R-ros SJ, KOKU .& WALGRAVZ SL: L o c a l i z a t i o n o f t h e Main Immunogenic Region of Human Muscle AceryIchoUne Rceptor to Residues 67-76 of the Alpha Subunit. Proc Null Acad Sci USA 1988, 85:2899-2903. MEIMS A, CHRF..STEL S, SCHALKE BC, WEKERLE H, MAURON A, BAUIVIZ M, BARKAS T: T Lymphocytes in Myasthenia Gravis.
Determination of Target Epitopes Using T Limes and Recombinant Products of the Mouse Nicotinic AcetylchoIine Receptor Gene. J Clin hues1 1989, 83~785790. 3. .
SOWER N, WILCOX
N, HARCOURT
GC, NRWSOM-DAVIS
J: Myas-
the& Thymus and Thymoma are SelectiveIy Enriched in Acetylcholine Receptor Specific T Cells. Ann Neurof 1990, 28312~319.
Documents the isolation OF AChR-specific T-cell lines from myasthenic thymuses (hyperplastic and neoplastic). Is this cause or consequence of the myasthenogenic pathogen&s? 4. .
ZHANC Y, SCHLUEP M, FRU~GER
S , HU G H E S G J , JEANNET
M,
S’IXCK A, BARKAS T: Immunological Heterogeneity of Autoreactive T Lymphocytes Against the Nicotinic Acetylcholine Receptor in Myasthenic Patients. Eur J Immunol 1990, 20:2577-2584. Epitope determination using peptide fragments of recombinant mammalian AChR. MG-derived. HIA DRZ-restricted T cells preferentially recognize sequence 162-216. 5.
SALWITI M, J UNG S. CHANG S-F, WIIL H, SCHAIJ@ BCG, WEKERLE H: Acetylcholine Receptor-Specific T Lymphocyte Clones in the Normal Human Immune Repertoire: Target Epitopes. HLA Restriction, and Membrane Phenotypes. Ann Neural 1991, 29:508-516. Reports the isolation of AChR-speciiic TceU lines from healthy donors using recombinant mammalian or native Torpedo AChR. Demonstration of potentially autoimmune T-cell clones in a normal immune repertoire. .
6.
. .
M@x A , O ’ CO N N O R R, G E U D E R Kl, H O P P E F, Sew BCG, Tz&xos S, KAU~ I , KIRCHNER T, MO-R-HERMEUNK HK: Char-
acterization of a Protein with an Acetylcholine Receptor Epitope Boom Myasthenia Gravis-associated Thyrnomas. Lab Ino& 1990, 62:27%2&i Most MGsssociated epitheUaI thymomas express a protein that bids a monoclonal antibody directed to a cytoplasmic AChR domain. The isolated protein dilfers, however, from human AChR, which may suggest ltlhkly.
J: Calcium Chan-
J, V I N C E N T
A: Passiie Transkr of Larnbert-Eaton Myasthenic Syndrome with IgG born Man to Mouse Depletes the Presynaptic Membrane Active Zones. Pror A’uff Acad Sci USA 1983, 80:7636-7640. DARNEU RB, FURNEA~~ RB, POSNER JB: Antiserum from a Patient with Cerebcllar Degeneration Identifies a Novel Protein in Purkinje Cells, Cortical Neurons, and Neuroectodermal Tumors. / Neurosci 1991, 11:1224-1230. Autoantibody binding to three molecules expressed in cerebeUar Purkinje cells, certain cortical neurons, and some neuroectodermal tumors. 9. .
R, POZZA G, DE CAMILLI P: Autoantibodies to GABA-ergic Neurons and Pancreatic Beta Cells in Stiff-man Syndrome. N EnglJ Med 1990. 322:155+1560. Autoantibodies from SMS patients bind to glutamic acid decarboxylase expressed in GABAergic neurons and in pancreatic B-cells.
10. . .
References and recommended reading
I, NRYSOM-DAVIS
nel Autoantibodies in the Lambert-Eaton Myasthenic Syndrome. Ann Neural 1991, 29:307-314. Most LEMS patients have serum antibodies against voltage-gated calcium channels, but (like in MG) autoantibody titers do not correlate well with dIsea5e swerig. Autoantibodies are heterogeneneous.
SOUMENA M, FOUI F, APAIUSI
11. . .
AUEGREITA
M, NCKIAS JA, S~~.AM S. AIBERTINI RJ: T Ceils Responsive to MyeIin Basic Protein in Patients with Multiple Sclerosis. Science 1990, 247:718-721. Isolation OF thioguanine-resistant, mutant T-cell clones from peripheral blood of MS patients. About 5% of these recognize MBP.
12.
OTA K , MAT%J~ M , MILFORO E L , MACKIN G A . W E I N E R HL, HAFL!zR DA: T-cell Recognition of an Irnmunodominant Mye-
.
Iin Basic Protein Epitope in Multiple Sclerosis. Nature 1990, 346:183187. Reports that T-cell lines from MS patients with HIA-DR2 haplotype pmferentiaUy react to MBP sequence 84-102 (46% of 302). A less pronounced epitope dominance in control T cells from normal donors (11%) is also reported as well as a second dominant epitope In sequence 143168. 13. .
PETJE M, FUJITA K, WILKINSON D, AL~MANN DM, TROW~DALE J, GIERGERICH G , HINKKANEN A , EPPLEN J T , KAp?os L, WEKER~E
H: MyeIin Autoreactivity in Multiple Sclerosis: Recognition of MyeIin Basic Protein in the Context of HLA-DR2 Products by T Lymphocytes of Multiple Sclerosis Patients and Healthy Donors. Proc Nat1 Acad Sci USA 1990, 87:7968-7972. Broad MBP epitope reactivity in T-cell lines from MS and normal donors as rweaied by HlA-DRZ gene transfected L ceils and MBP peprides. The DR2a molecule presents at least four peptides. 14.
.
MARTIN R, HOWEU MD, JARAQUEMADA D, FLER~AGE M, RICHERT J, BRO~TO~~ S , L O N G E O , MCFARUN D E , MCFARIAND HF: A
MyeIin Basic Protein Peptide is Recognized by Cytotoxic T Cells in the Context of Four HLA-DR Types Associated with Multiple Sclerosis. / Exp A4ed 1991, 173:19-24. Documents heterogeneous epitopes recognized by four T-cell Unes spe cific for MBP sequence 89-99 and an equaUy broad TCR V gene usage. 15. l .
WUCHERPFENNIG KW, OTA K, ENDO N, SEIDMAN JG, R~~ENZWEIG A , WEINER HI, HAFLER DA Shared Human T CeU Receptor Vj3 Usage to hnrnunodominant Regions of Myelin Basic Protein.
Science 1990, 248:101&1019. Expansion of VB17 using MBP (sequence 84-102)speciiic TceU lines in some MS patients. In another patient similar Unes prefer use of VBl2. No clear VB preference in peptide 143166.specilic T ceUs is reported. Documents a poiymemse chain rearion study with sequences. 16. l
BEN-NUN A , Lml~u RS, C O H E N L, L E H M A N N D , TOIJRNIER~ASSERVE E, ROSENZWE~G A, JLNG~ 2, Iuus JCM, BACH M-A: Re~stricted T-cell Receptor VB Gene by Myelin Basic Protein-
Specilic T-cell Clones in Multiple ScIerosis: Predominant Genes Vary in ImEviduais. Pnx NaU Acad Sci USA 1991, 88:2466-2470. Reports the dominance of VP15 gene in T-cell clones derived from one poiyclonal MS-derived ~anti-MBP T-cell Une recognizing sequence 149-162. Also documents a PCR study of TCR rearrangement patterns.
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Autoimmunity 17. .
C HOU YK, HENDERIK~ P. VAINIE~% M, WH~THA&I R, BOURDETIF D, CHOU CH-J, ~-LUHIM G, OFFMR H, VANDENBAR~; fi Specificity of Human T Cell Clones Reactive to Immunodominant Epitopes of MyeUn Basic Protein. / Neuracii Res 1991. 28:28&290. Reports VP5 usage in four out of eight T-cell clones (different target epiropes) derived from one MBP-specific T-cell line from an MS parienr (HLA-DR2). Also document? TCR typing using a monoclonal antibody.
terminant on MyeUn and Oligodendrocytes, and Augments Demyelination in Experimental Allergic Encephalomyelitis. J &.\p Med 1990, 171:18931908. Repons BALB/c mouse-derived monoclonal antibodies recognizing both TMEV and galactoscerebroside epiropes. The monoclonal antibody binds to MBP-expressing oligodendroc)qes hf chq and to myelin in brain sections. When injected into a mouse with EAE. it causes demyeelination.
18. .
31. .
WUCHERPWNNlC KW, WEtNER HL, HAFLER DA: T-cell Recognition of Myelin Basic Protein. fmmunol To@ 1 9 9 1 , 12~277-282. Discussion of MBP as an autoantigen in MS, and summary of epirope recognition and TCR gene usage by MS-derived T-cell clones, 19. .
OK~ENBERC JR, STUART S, BEGOXH AB, BELL RB, ERLICH kh STElNhlAN L, BEMARD CCA: Limited Heterogeneity of Rearranged T-cell Receptor Vu Transcripts in Brains of Multiple sclerosis Patients. Nature 1990, 345~344-346. PCR amplification of Vu gene transcripts from MS autopsy brains. Preferential ampIification of Vp12.1. 20.
YAMM~URA T, NAMIKA%~A T , ENDOW M, KUNISHITA T. TABIRA T: Passive Transfer of Experimental Allergic Encephalomyelitis Induced by ProteoUpid Apoprotein. J Neural Sci 1986, 76:269-275.
21.
SATO J, S%u K. ENWH M, KoltcE F, KLIN~SHITA T. N~UKAWA T , T~URA T , TABIRA T: Experimental Allergic Encephalomyelitis Mediated by Murine Encephalitogenic T Cell Limes SpecUic for Myelin ProteoUpid Apolipoprotein J Immunol 1987, 138:179-184.
22.
-i-UOHY WC, LU ZJ, SoBEl. RA, ~URSEN RA, LEES MB: A Synthetic Peptide from Myelin Proteolipid Protein Induces Experimental AUergic Encephalomyelitis. J fmmunol 1988, 141:1126-1130.
WHITHAM RH, BOURD~E DN, HASHIM GA, HERNDON GM, ILG RC, VANDENBARK AA, OFFNER H: Lymphocytes Tom SJL/J Mice Immunized with Spinal Cord Respond Selectively to a Peptide of ProteoUpid Protein and Transfer Relapsing Demyelinating Experimental Autoimmune Encephalomyelitis. ~_ J Immunol 1991. 146:101-107. T cells from spinal cord immunized SJVJ mice with EAE preferentially respond to PLP (synthetic peptides 139151 and 141-151) rather than to MBP epitopes. PLP may be the dominant encephalitogen in SJUJ mice. 23. . .
24.
KEENEDY MK, T A N L - J , DA L C A N T O M, Tuo~v V , L u Z , TROTTER JL, MILLER SD: Inhibition of Murine Relapsing Experimental Autoimmune Encephalomyetitis by Immune Tolerence to Proteolipid Protein and its Encephalitogenic Peptides. J Immunol 1990, 144909-915.
25. .
PERR( 4 BARZAGA-GILBERT E, TROT~FR JL: T CeU Sensitization to ProteoUpid Protein in Myelin Basic Protein-Induced Relapsing Experimental AUergic EncephaIomyeUtis. J Neumfmmunol 1991, 33:7-15. Induction of relapsing EAE in Fl(SJVJ X PI/J> hybrid mice with MBP. Demonstration of PLP-specific T cells following acute EAE episode. 26.
27.
SCHLUE~ENER HJ, WEKEIUE H: Autoaggressive T Lymphocyte Limes Recognizing the Encephalitogenic Region of MyeUn Basic Protein: In Vftro Selection from Unptimed Rat T Lym phocyte Populations. J Immunof 1985. 135:3128-3133. B URNS J, ROSENZSVEIG A, ZWEIMAN B USAK RP: Isolation of Myelin Basic Protein-recative T-cell Lines from Normal Human Blood. Cell Immunoi 1983, 81:435-%0.
28.
TOURNIER&USERVE E, HASHIM GA, BACH MA Human T-cell Response to Myelin Basic Protein in Multiple Sclerosis Patients and Healthy Subjects. / Neurozi Res 1988,19:149-156.
29.
FUR RS, OIDSTONE MB: Amino AcidHomology between the Encephalitogenk Site of MyeUn Basic Protein and Viis: Mechanism for Autoimmunity. Science 1985, 230:1043-1045.
30. . .
YAMADA M, ZURBIUGGEN A, ~QINAMI RS: Monoclonal antibody to Theiks Murine Encephalomyelitis Viis Defines a De-
SINGIi c1<, w HK, YAMAKI K. ABE T. D0NO.so 14 SHINOHAR\ T: Molecular Mimicry between a Uveitopathogenic She of S-antigen and Viral Peptides. Induction of Experimrntal Autoimmune Uveitis in Lewis Rats. J fmmunol 1990. 144:1282-1287. Lewis rat T cells co.recognize the uveitogenic S-protein and hepetitis B virus peptides. 32.
SAUI K. TABIRA T, K~JNISHITA T: Recognition of AUoantigens and Induction of Experimental Allergic Encephalomyelitis by a Murine Encephalitogenic T-cell Clone. Eurj Immunol 1987, 17:955%.
BEN-NLIN A: Staphylococcal Enterotoxin B as a Potent Supressant of T CeU Proliferative Responses in Rats. Eftr J Imtnunol 1991, 21:815-818. SEB is a poor mitogen in the Lewis rat although in vitro it may interfere profoundly with encephalitogenic inducibility of MBP-specific T cells. 33. .
34. .
BOYWI’ KB, TAKAHASHI N, PAT-Y DB, .%DO~NNIK AD, DIAMOND M. HOOD I+ PRLISINER SB: DNA Length Polymorphism 5’ to the MyeUn Basic Protein Gene is Associated with Multiple Sclerosis. Ann Nerrrol 1990, 271291-297. Ten alleles identified in the lirsr human MBP exon on chromosome 18. Increased occurrence of certain alleles in MS patients. This is an RFLP Study.
35. .
HILIXRT J, &NC C, OLERUP 0: No Association with Germline T CeU Receptor J3 Chain AIIeles or Haplotypes in Swedish Patients with Multiple Sclerosis. J Neuroimmunol 1991, 31:141-147. RFLP analaysis of 100 MS patients (23 chronic progressive, 77 relapsing/remitting). No association with allelk pattern or TcR P.chain gene haplotypes is reported. 36.
MARCADET A, GEBUHRER L, BETUEL H, SEIGNALET J, FREIDEL AC, CONFAVREUX C , BILLIARD M DAU~~ER J, C OHEN D: DNA Poly morphism Related to HLA-DR2 Dw2 in Patients with Narcolepsy. lmmunogen 1985, 22:67‘+683.
37.
Loclc CB, So AK, WELSH KI, PARKES JD: MHC Class II Sequences of an HLA-DR2 Narcoleptic. Immunogen 1 9 8 8 , 2744955.
38. .
MIGNOT E, W A N G C , RATIXXI C , GAISER C , Lovzrr M , GU1UMINALJI.T C, DEMENT W C , GRUMET FC: Genetic Linkage of Autosomal Recessive Canine Narcolepsy with a p Immunoglobulin Heavy Chain Switch-like Segment. PI-CC Natf Acad Sci LX4 1991, 88:3475-3478. Restriction fragment length polymorphism mapping of a canine narcolepsy-associated gene to immunoglobulin nearly chain switch gene; no association with MHC class II, as in human narcolepsy. 39. .
O~SSON T, ZHI WW, HOJEBERG 8, Kosrul~s V, Yu-Pmc J, ANDERSON G, EKRE H-P, LINK H: Autoreactive T Lymphocytes Secretion of Interferon-y. J Clin Invest 1990, 86:981-985. Demonstration of activated, cytokine-secreting T cells in CNS of MS patients using an ‘immunospot’ technique. 40. .
SE~MAJ K, RAWE CS, CANNEUA B, BROSNAN CF: Identilication of Lymphotoxin and Tumor Necrosis Factor in Multiple Sclerosis Lesions. J Clin Invest 1991, 87:949-954. lmmunocytochemical visualization of TNF-a and TNF-j3 in MS brain sections. TNF-a is mainly associated with astrocytes and macrophages, and with some endothelia of active lesions. TNQ is found on CD3 T ceUs and microglia cells. 41. . .
SHAIUEF MK, HJXXES R: Association Between Tumor Necrosis Factgor-a and Disease Progression in Patients with Multiple Sclerosis. N Engl J Med 1991, 325~467472.
Neuroloaical Documents a prospective 2 year study of TNF-a titers in the CSF of 52 patients with active MS, 20 with remitting MS and 85 other neurological patients. Reports .some correlation between TNFa titers in CSF and disease severity. This may result from intrathecal cytokine production. FREI K, FREDRUCSON S, FONTANA A, LINK H: Interleukin-6 is Elevated in Plasma in Multiple Sclerosis. / Nezrrohnmzrnof 1991. 31:147-153. In MS, IL.6 titers are higher in plasma than in CSF. The converse situation is seen in tiral encephalitis.
Documents human HlA-DR2 haplotype associated with low production of TNFa and with susceptibility to nephritis in systemic lupus erythematosus. 50.
Drl~~hl I, SARGE~ CA, THOWSDA~~ J, CA~IPBEU RD: Molecular Mapping of the Human Major Histocompatibility Complex by Pulsed-field Gel Electrophoresis. Proc Nat1 Acad Sci @iA 1987, 84~7237-7241.
51.
CAHOU.
42. .
43.
MhlhiONE
D, GREGORY
s, hNASON BGW,
REDEH
44.
AT CytOkiIX
FOKTANA A, K~USIXNSEN F, D~IRS R, GIZMSA D. WERER E: Production of RostaglandIn E and an Interleukin-I like Factor by Cultured Astrocytes and C6 Glioma Ceils. J fntmunol 1982. 129:2413-2419.
45.
BORBELY
46. . .
SPRANCEH M, LLNDHo~M D. BANDTLOW C. HEIJMANN R , GNAHN ii, NAHER-Noti M, THOENEN H: Regulation of Nerve Growth Factor (NGF) Synthesis in the Rat Central Nervous System Comparison Between the Effects of Interleukin-I and Vatious Growth Factors in Astrocyte Cultures and In Vivo. Ezrr
AA, TOHIER I: Endogenous Sleep-promoting Substances and Sleep Regulation. P/gsiol Ret! 1989, 69:605-670.
J Neuraui 1990, 269-76.
Rapid induction of NGF expression in astrocyte cultures and in situ by IL-l. Autocrine induction of IL-1 synthesis in CNS. The study was carried out using in tiiu hybridization and northern blot analysis techniques. B ROWN MC, PERRY VH, LUNN ER, GORDON S, HELIW R: Macrophage Dependence of Peripheral Sensory Nerve Regeneration: Possible Involvement of Nerve Growth Factor. Neuron 1991, 6359-370. Reports that WaIlerian degeneration in C57~uOla mutant mice is slow, and associated with a relative lack of inhltrating macrophages. Expres sion of nerve growth factor (NGF) and NGF receptor mRNA is also reported to be abnormally low. 47. .
48. .
K~MATA H, YOSHIDA 4 IS~OKA C, KUSUNOKI
T, Moser S, ~~IKAWA
H: Nerve Growth Factor Specificially Induces Human IgG4 Production. Eurj lmtntcnol 1991, 21:137-141. NGF specifically enhances production of 1gG4 isotype in human tonsiliar lymphocyte cultures. T-cell help is required. 49. .
JACOB CO, FRONEK 2, LEYIS CD, Koo M, HANSEN JA, McDE~T~ HO: Heritable Major Histocompatibiity Complex B-associated Differences in Production of Tumor Necrosis Factor a: Relevance to Genetic Predisposition to Systemic Lupus Etytbematosus. Proc Nail Acud Sci USA 1990, 87:1233-1237.
MC, KAJAR P, AucOT EM, KOUER BH, GERACHTY
DE
ORR HT, STROMINGER HL, SPIES T: Linkage Map of the Human Major HistocompatibIIty Complex Including the Tumor Necrosis Factor Genes. Proc Nat1 Acad Sci UU 1987, 848535-8539.
.
Levels in the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis. J Neuraimmrcnol 1991, 3267-65. IL.~ and TNF-a titers are elevated in the CSF of MS patients. but also in other inUa.mmatory CNS diseases. No correlation with oligoclonal immunoglobulins in CSF is reported.
diseases Wekerle 901
LAsshwNN
H, ROWER K, Zthl~%~c~ F, V.&z& K: Expression of Adhesion Molecules and Histocompatibility Antigens at the Blood-Brain Barrier. Brain Pafbol 1991, 1:115-123. Excellent raiew of in situ expression of cell adhesion molecules, including members of the immunoglobulin gene superfamily. 52. .
RA, MI T CHELL ME, FONDREN G: Intercellular Adhesion Molecule-l (ICAM-1) in Cellular Immune Reactions in the Central Nervous System. Am J Pafhf 1990, 136:1309-1316. Strong expression of CAM in MS lesions. Intercellular adhesion molecule (ICAM)-l is on membranes of microvessel, some glia cells, and infiltrate cells. In contrast, the ICAM. @and lymphocyte function. associated antigen-l is expressed solely on mononuclear ceUs. 53. .
SOBEL
CF, RAUW CS: Hypotbesis: Antigen-specific T CeUs Prime Central Nervous System Endothelium for Recruitment of Nonspecific I&lammatory Cells to Effect AutoImmune DemyeIination. J New roimmunol 1991, 33:237-244. On the basis of the author’s own morphological work it is suggested that antigen-specific T cells prime CNS endothelium for recruitment of nonspecific intlammatory cells to effect autoimmune demyelination.
54. .
CROSS AH, CANNEUA B, BROSNAN
55. OSBORN L Leukocyte Adhesion to Endothelium In InIlam. mation. Cell 1990, 62:2&6. Useful introduction to human ceU adhesion molecules involved in rectuitment of inUammatory cells into tissue lesions. DANA N. FATWUMH DM, ARNAOUT MA Expression of a Soluble and Functional Form of the Human 02 Integrin CDIlWCDlS. Proc Nat1 Acad Sci USA 1991, 88:310&3110. Reports engineering of integrin genes, which may lead to therapeutic manipulation of ir&tmmatory ceU recirculation. 56. .
H Wekerle, Max-Planck Institute for Psychiatry, Klopferspitz 18, D-8033, Martinsreid, Munich, Germany.
Wekerle
Max-Planck Institute for Psychiatry, Munich, Germany
Recent advances have improved our understanding of the T-cell recognition process in neuroimmunological autoimmune disease as well as the involvement of major histocompatibility complex molecules and cell adhesion molecules in the autoimmune attack.
Current Opinion in Immunology 1991, 3:896-901
Introduction
Autoantibodies
The number of neurological diseases in which an autoimmune pathogenesis is suspected is considerable. The number of disorders in which autoimmune mechanisms have been proven is much fewer. These autoimmune mechanisms may be identified by autoantibodies that bind to defined structures, and mediate disease following adoptive transfer.
Myasthenia
Central nervous system (CNS) autoimmunity in the absence of humoral autoantibodies is more diEcult to determine. In multiple sclerosis (MS), for example, autoimmunity has been suggested by histology, MHC-linked susceptibility and similarity to experimental autoimmune encephalomyelitis (EAR) models. Other diseases, such as narcolepsy, are suspected to have an autoimmune component solely because of their peculiar genetic control. Thus, the discovery of a large number of autoimmune diseases of the nervous system may be anticipated. Research Into autoimmunity within the nervous system is by no means restricted to neuroimmunology. A better understanding of cellular immunology and autoimmunology in general has also been gained. RAE models were the Iirst to allow the establishment of autoaggresslve T-lymphocyte lines, which may be used as probes to provide Invaluable Insights into epitope recognition, TCR gene usage, and T-cell-directed imrnunotherapies. This trend seems to be continuing, possibly with a certain shift of the main objectives. Although the T-cell recognition process was considered to be the most exciting feature of neuroimmunological autoimmune research, many workers now address other issues such as regulation of MHC expression in the target tissues and cell adhesion molecules Involved in the autoimmune attack. .-
in
neurological
diseases
gravis
Myasthenia gravis (MG) was the first, and still is the best characterized neurological disease resulting from pathogenic autoantibodies. It is undisputed that ‘spontaneously’ arising autoantibodies, many of which are directed against an epitope cluster, ‘main immunogenic region’ (ME), located within a circumspect sequence area of the acetylcholine receptor (AChR) a-chain [ 11, are responsible for the neurological defects that are typical of the disease. The stimulus for autoantibody production in MG is unknown. The very strict association of the disease with abnormalities in the thymus has suggested that the first step of autosensitization occurs within the thymus. Indeed, the prevailing MG-related thymus lesion, thymic hyperplasia, provides the key requirements for local T helper cell activation. It contains AChR-producing myoid cells, antigen-presenting interdigitating cells arranged in a particular spatial pattern [ 21, as well as a relatively high number of AChR autoreactive T cells (3-l. Intrathymic activation of AChR-speci6c T cells with subsequent helper effect on AChR-reactive B lymphocytes would account for these findings. Peptide epitopes have been mapped on a number of MG-derived anti-AChR T-cell clones [4*]. But AChR-specific T-cell clones are not at all speciiic for MG, although they can be isolated from the peripheral blood of healthy donors, and are, therefore, components of the normal T-cell repertoire [ 5.1. The role of neoplastic thymus changes in MG was obscure until recently. The group of Miiller-Hermelink [6**] first demonstrated serological cross-reactivity of thymoma epithelial membranes with anti-A&R monoclonal antibodies that were directed against cytoplasmic epitopes.
Abbreviations AebR-acetylcholine receptor; BBB-blood-brain barrier; CAM-cell adhesion molecule; CNS-central nervous system; PAP-experimental autoimmune encephalomyelitis; IL-interleukin; lEh4S-Lambert-Eaton myasthenic syndrome; MBP-myelin basic protein; MC-myasthenia gravis; MIR-main immunogenic region; MS-multiple sclerosis; NCF-nerve growth factor; PLP-proteolipid protein; PNS-peripheral nervous system; MS-stiff-man syndrome; TCR-T-cell receptor; TNF-tumor necrosis factor.
@ Current Biology Ltd ISSNO952-7915
Neurological
These *analyses indicated that the membrane antigen involved is not related to the AChR gene family, but that the cross-reaction reflects an unexpected case of molecular mimicry. It is possible that T cells which recognize the peptide sequence shared between thymoma protein and AChR may activate B cells, producing genuine anti-AChR autoantibodies in a second step.
lambert-Eaton
myasthenic syndrome
Thanks to the work of Newsom-Davis and colleagues [7=], the Iarnben-Eaton myasthenic syndrome (LEMS), a rare presynaptic disturbance of neuromuscular transmission has been characterized as a second example of autoantibody-mediated disease peripheral nervous system (PNS). These workers demonstrated the pathogenic effect of LEMS-derived autoantibodies in in vim transfers
[81. Recently, it has become clear that the molecular target of LEMS autoantibodies is the presynaptic calcium transport system and binding occurs to calcium channels in vitro [7*], and presumably in zlivo. In other neurological diseases, autoantibodies against CNS components have been demonstrated, without formal proof of their pathogenic character. In paraneoplastic cerebellar degeneration, for example, autoantibodies that bind to neuronal structures, e.g. Purkinje cells, have been found [9*]. The mechanism of action of these autoantibodies has not been determined. It is still unclear how the autoreactive immunoglobulins cross the bfood-brain barrier and, in addition, it is hard to explain how they can cross the target-cell membrane to reach the intracellular autoantigens. A most Intriguing case of putative autoimmune CNS disorder is ‘stiff-man syndrome’ (SMS). Autoantibodies against glutamyl decarboxylase, an enzyme involved in the metabolism of GABA, have been found in at least some patients with SMS. Interestingly, similar autoantibodies were demonstrated in patients with autoimmune diabetes mellitus, which may explain the occasional link between these disorders [lo**].
T cells in neurological diseases: MS as a paradigm In MS as is any cell-mediated human autoimmune disease, the definitive proof of the causal involvement of autoaggresive T lymphocytes would be made by transfer experiments which, for obvious reasons, are impossible to carry out. Thus, evidence for the autoimmune nature of MS is indirect and includes the characteristic histological features of the lesion, and the striking sUnilarity to some variants of an autoimmune model disease, EAE. More recently, one group found evidence for an increased frequency of somatic mutations in myelin basic protein @BP)-specific T-cell clones from MS patients, which was thought to reflect strong proliferation, as a consequence of an autoimmune reaction [ 1 l**] .
diseases
Wekerle 897
Several groups have isolated myelin-specific T lyrnphocytes to characterize the autoimmune pathogens of MHCrestricted recognition of myelin epitopes [12.-14’1 and their use of T-cell receptor (TCR) variable region genes [14.,15**,16*,17*]. These studies were inspired by work in rodent EAE, which established that the autoaggressive T-cell clones were directed against a very narrow spectrum of dominant target epitopes, and used a limited repertoire of T-cell receptor V region genes [ 18.1. Results from studies in humans have been unexpectedly disparate. Some groups have noted dominating epitopes in the carboxy-terminal part of MBP, others in the central part, whereas still others found codominance of these peptide sequences, or reactivity against multiple epitopes placed all along the MBP molecule [13*,18*]. Epitope mapping under highly defined conditions (use of human MHC transfectants as antigen-presented cells [13*,14*] will be required to define epitope preference in the human anti-MBP response. Clearly, however, there is no cogent evidence of an MBP epitope that is associated with T cells from MS patients speciEcaUy. In certain strains of rodents, encephalitogenic, MBP-specific T cells use very narrow repertoires of TCR genes, a finding that has given rise to novel TCR-targeted vaccination strategies (reviewed by Weiner et al. pp 936940). TCR dominance has been reported in MS plaque i<rates [ 19.1, which suggests that T cells inIiltrating MS brain tissue use a limited repertoire of TCR V genes. The specificity of these cells has not been determined, however. TCR analyses of myelin-specific human T-cell clones has revealed a more intricate pattern of gene usage. Expansion of MBP-specilic T-cells clones using identical V genes has been reported in several MS patients and in other cases, a broader spectrum of TCR gene usage has been seen [l@] (Giegerich et al, submitted for publication).
Activation of autoimmune T cells by autoantigens, molecular mimicry and superantigens Until very recently, most autoImmunologIsts were convinced that MBP was unique in eliciting a myelin-directed autolmmune attack within the CNS. Over t.ha past ?few years, however, other structures, particularly proteolipid protein (PLP), have been reported to be potential encephalitogens. Work carried out in the fifties by Waksman and Lees indicated that PIP might be a key encephalitogen, at least in some species or some individuals. Further evidence for this was provided by T-lymphocyte line transfers into the Lewis rat [20] and the SJL mous@[21], and through active Induction of EAE by synthetic PLP peptides [ 221. Recently, it was found that SJI/J mice Imtnunized with crude spinal cord homogenate have preferential activation and expansion of PLP rather than MBPspecUic T-cell clones [23m*] and mice tolerized against
898
Autoimmunity
PLP (but not against MBP) are resistant to RAE induction by spinal cord homogenate [ 241. There is evidence that in chronic relapsing RAR of the Fl(SJI./J x PI/J) hybrid mouse initial MBP-specific T-cell triggers may activate subsequent anti-PLP T-cell responses [25*]. Activation of autoimmune encephalitogenic T-cell clones, which are components of the intact rat [27] and human [9’,10**,27,28] immune system is a rare event considering the low incidence of spontaneous FXE and MS. As ptimary immunization of these clones by antigen presentation by CNS glia is not very likely, other peripheral mechanisms should be investigated as stimuli for the pathogenic T-cell responses. Molecular mimicry is one of these mechanisms. Fujlnami and Oldstone [29] were the lirst to provide evidence for viral peptides cross-activating MBP-specific, encephalitogenlc T-cell clones to trigger EAR. More recently, humoral autolmmune mimicry reactions were found to participate in the subacute vnriant of Theiler’s virus encephalitis [30..]. T-cell mimicry responses were also noted between uveitogenic peptides and viral [31-J sequences. An alternative method for activating pathogenic T-cell clones could involve microbial ‘superantigens’. Sakai et al [32] reported that encephalitogenic T-cell clones from SJL/J mice ‘co-recognized’ allogeneic Mls determinants [33*]. After the recent description by Ben-Nun [ 341 of interactions of staphylococcal enterotoxins (negative) with encephalitogenic T-cell clones the first demonstration of superantigen-triggered RAE is awaited with much interest.
Genetics
Much work has been devoted to identifying genetic factors predisposing to autoimmune susceptibility. In the case of neurological diseases, most of these studies have provided Interesting results, but are still far from identifying ‘the’ MS susceptibility gene. The three molecular components of the MBP/T-cell recognition complex have been screened for genetic polymorphisms that may be affiliated with MS. There is an MBP-gene polymorphism, which seems to be overrepresented ln MS patients [3+]. TCR gene polymorphisms were screened by several groups and restriction fragment length polymorphism RPLP studies indicated the occurrence of certain TCR allotypes ln some populations [35*]. Attempts to further investigate the MHC-related MS ‘disease gene(s)’ have been frustrating. Immunogenetics may be of more use in the illumination of the pathogenesis of narcolepsy. Narcolepsy, characterized by a profound disturbance of sleeping behavlour was surprisingly found to be associated with an HLA-DR2 haplotype- [36]. This finding led to a detailed scrutiny of the human HLA D region, which did not identify any abnormal genes [37]. Although there is no formal evidence of lmmunopathologlcal mechanisms in narcolepsy, its close association with DR2 haplotypes, and the recent demonstration of a linkage in canine narcolepsy [38*]
maintains interest in the search for (auto-) immune factors.
Cytokines
Because cytokines are essential in orchestrating the cellular autoimmune attack against autoantigens, much attention has been devoted to their study in autoimmune diseases and in models for these diseases. In MS, products of activated T cells such as IL-2, interferon (IFN)-)I, and ThFa (a mediator produced by T cells and macrophages) have been demonstrated [ 39*,40*,41**]. Furthermore, cytokines; such as IL-1 and IL-~ [42*,43*], which are produced by a variety of cells are found in increased amounts in CNP/PNS autoimmunity. Cytokine elevation is, however, also seen in other intlammatory disorders of the CNS. In addition to their role as mediators between (auto-) immune cells, cytokines may have functions that are specilic to the nervous system. Many cytokines directly bind to structures within the nervous system, and at least some of these are produced by local glia cells. The work of Fontana et all [44] first indicated that glia cells, and among them astrocytes and rnicroglia cells are efficient producers of cytokines including IL-1 [30]. There is evidence that at least some cytokines are involved in physiological linking of the CNS to the immune system. IL-l, for example, is known to have a profound impact on sleeping behaviour [45**]. Furthermore, the interplay of cytokines with nexve growth factors have been identified recently. Studies by Thoenen’s group have provided evidence for a more general function of cytokines and IL1 has a profound effect on regulation of nerve growth factor in the CNS [46**]. Macrophages are required to trigger the intact program of cellular regeneration in CNS and PNS 147.1, and cytokines secreted by these macrophages may be involved as mediators. Conversely, nerve growth factor seems to have effects on diverse immune cells and thus may modulate immune functions [48-l. This, however, remains to be analyzed in detail. TNF-a may have a function in effector mechanisms that lead to demyelination and gliosis [40*,49]. This contention is supported by a recent study that demonstrated a close association between the course of MS and TNFa levels in the CSF [41**]. the TNF-a gene is located within the human HIA gene complex and shows polymorphisms, which might be related to certain autolmmune disease [49]. How similar polymorphisms may control susceptibility to MS or other inflammatory diseases of the CNS remains to be elucidated.
Cell-adhesion
molecules
Research into cell-adhesion molecules (CAM S) is progressing rapidly. CAMS have crucial roles in the development and in the maintenance of the nervous system. They are involved ln directing guiding axonal growths proper
Neurological diseases Wekerle 899
association of glia cells between each other with neurons. In addition, CAMS mediate interactions with the immune cells that are required for entry into the CNS and their communication with CNS cells in immune surveillance and autoimmune disease (35.1. Particular attention has been paid to the expression of CAM in MS plaques [ 36.1, where they may be involved in autoantigen presentation and cellular effector mechanisms Another focus of CAM expression is the blood-brain barrier (BBB) [37-l. Here, inducible CAMS are of interest [38-l because they may be involved in guiding circulating immune and inflammatory cells into the CNS, and thus co-determining the fate of an intracerebral inflammation. Production of soluble inhibitors may be a promising novel strategy to interfere with BBB traffic in MS and other inflammatory brain disorders 139’1.
7. .
Lm K, IANG B, JOHNSTON
8.
FUKLJNAGA H, ENGEL AG, LANG B, NRYSOM-DAVIS
Papers of have been . of . . of 1.
2.
special interest, published within the annual period of review highlighted as: I interest outstanding interest
Tzr\R-ros SJ, KOKU .& WALGRAVZ SL: L o c a l i z a t i o n o f t h e Main Immunogenic Region of Human Muscle AceryIchoUne Rceptor to Residues 67-76 of the Alpha Subunit. Proc Null Acad Sci USA 1988, 85:2899-2903. MEIMS A, CHRF..STEL S, SCHALKE BC, WEKERLE H, MAURON A, BAUIVIZ M, BARKAS T: T Lymphocytes in Myasthenia Gravis.
Determination of Target Epitopes Using T Limes and Recombinant Products of the Mouse Nicotinic AcetylchoIine Receptor Gene. J Clin hues1 1989, 83~785790. 3. .
SOWER N, WILCOX
N, HARCOURT
GC, NRWSOM-DAVIS
J: Myas-
the& Thymus and Thymoma are SelectiveIy Enriched in Acetylcholine Receptor Specific T Cells. Ann Neurof 1990, 28312~319.
Documents the isolation OF AChR-specific T-cell lines from myasthenic thymuses (hyperplastic and neoplastic). Is this cause or consequence of the myasthenogenic pathogen&s? 4. .
ZHANC Y, SCHLUEP M, FRU~GER
S , HU G H E S G J , JEANNET
M,
S’IXCK A, BARKAS T: Immunological Heterogeneity of Autoreactive T Lymphocytes Against the Nicotinic Acetylcholine Receptor in Myasthenic Patients. Eur J Immunol 1990, 20:2577-2584. Epitope determination using peptide fragments of recombinant mammalian AChR. MG-derived. HIA DRZ-restricted T cells preferentially recognize sequence 162-216. 5.
SALWITI M, J UNG S. CHANG S-F, WIIL H, SCHAIJ@ BCG, WEKERLE H: Acetylcholine Receptor-Specific T Lymphocyte Clones in the Normal Human Immune Repertoire: Target Epitopes. HLA Restriction, and Membrane Phenotypes. Ann Neural 1991, 29:508-516. Reports the isolation of AChR-speciiic TceU lines from healthy donors using recombinant mammalian or native Torpedo AChR. Demonstration of potentially autoimmune T-cell clones in a normal immune repertoire. .
6.
. .
M@x A , O ’ CO N N O R R, G E U D E R Kl, H O P P E F, Sew BCG, Tz&xos S, KAU~ I , KIRCHNER T, MO-R-HERMEUNK HK: Char-
acterization of a Protein with an Acetylcholine Receptor Epitope Boom Myasthenia Gravis-associated Thyrnomas. Lab Ino& 1990, 62:27%2&i Most MGsssociated epitheUaI thymomas express a protein that bids a monoclonal antibody directed to a cytoplasmic AChR domain. The isolated protein dilfers, however, from human AChR, which may suggest ltlhkly.
J: Calcium Chan-
J, V I N C E N T
A: Passiie Transkr of Larnbert-Eaton Myasthenic Syndrome with IgG born Man to Mouse Depletes the Presynaptic Membrane Active Zones. Pror A’uff Acad Sci USA 1983, 80:7636-7640. DARNEU RB, FURNEA~~ RB, POSNER JB: Antiserum from a Patient with Cerebcllar Degeneration Identifies a Novel Protein in Purkinje Cells, Cortical Neurons, and Neuroectodermal Tumors. / Neurosci 1991, 11:1224-1230. Autoantibody binding to three molecules expressed in cerebeUar Purkinje cells, certain cortical neurons, and some neuroectodermal tumors. 9. .
R, POZZA G, DE CAMILLI P: Autoantibodies to GABA-ergic Neurons and Pancreatic Beta Cells in Stiff-man Syndrome. N EnglJ Med 1990. 322:155+1560. Autoantibodies from SMS patients bind to glutamic acid decarboxylase expressed in GABAergic neurons and in pancreatic B-cells.
10. . .
References and recommended reading
I, NRYSOM-DAVIS
nel Autoantibodies in the Lambert-Eaton Myasthenic Syndrome. Ann Neural 1991, 29:307-314. Most LEMS patients have serum antibodies against voltage-gated calcium channels, but (like in MG) autoantibody titers do not correlate well with dIsea5e swerig. Autoantibodies are heterogeneneous.
SOUMENA M, FOUI F, APAIUSI
11. . .
AUEGREITA
M, NCKIAS JA, S~~.AM S. AIBERTINI RJ: T Ceils Responsive to MyeIin Basic Protein in Patients with Multiple Sclerosis. Science 1990, 247:718-721. Isolation OF thioguanine-resistant, mutant T-cell clones from peripheral blood of MS patients. About 5% of these recognize MBP.
12.
OTA K , MAT%J~ M , MILFORO E L , MACKIN G A . W E I N E R HL, HAFL!zR DA: T-cell Recognition of an Irnmunodominant Mye-
.
Iin Basic Protein Epitope in Multiple Sclerosis. Nature 1990, 346:183187. Reports that T-cell lines from MS patients with HIA-DR2 haplotype pmferentiaUy react to MBP sequence 84-102 (46% of 302). A less pronounced epitope dominance in control T cells from normal donors (11%) is also reported as well as a second dominant epitope In sequence 143168. 13. .
PETJE M, FUJITA K, WILKINSON D, AL~MANN DM, TROW~DALE J, GIERGERICH G , HINKKANEN A , EPPLEN J T , KAp?os L, WEKER~E
H: MyeIin Autoreactivity in Multiple Sclerosis: Recognition of MyeIin Basic Protein in the Context of HLA-DR2 Products by T Lymphocytes of Multiple Sclerosis Patients and Healthy Donors. Proc Nat1 Acad Sci USA 1990, 87:7968-7972. Broad MBP epitope reactivity in T-cell lines from MS and normal donors as rweaied by HlA-DRZ gene transfected L ceils and MBP peprides. The DR2a molecule presents at least four peptides. 14.
.
MARTIN R, HOWEU MD, JARAQUEMADA D, FLER~AGE M, RICHERT J, BRO~TO~~ S , L O N G E O , MCFARUN D E , MCFARIAND HF: A
MyeIin Basic Protein Peptide is Recognized by Cytotoxic T Cells in the Context of Four HLA-DR Types Associated with Multiple Sclerosis. / Exp A4ed 1991, 173:19-24. Documents heterogeneous epitopes recognized by four T-cell Unes spe cific for MBP sequence 89-99 and an equaUy broad TCR V gene usage. 15. l .
WUCHERPFENNIG KW, OTA K, ENDO N, SEIDMAN JG, R~~ENZWEIG A , WEINER HI, HAFLER DA Shared Human T CeU Receptor Vj3 Usage to hnrnunodominant Regions of Myelin Basic Protein.
Science 1990, 248:101&1019. Expansion of VB17 using MBP (sequence 84-102)speciiic TceU lines in some MS patients. In another patient similar Unes prefer use of VBl2. No clear VB preference in peptide 143166.specilic T ceUs is reported. Documents a poiymemse chain rearion study with sequences. 16. l
BEN-NUN A , Lml~u RS, C O H E N L, L E H M A N N D , TOIJRNIER~ASSERVE E, ROSENZWE~G A, JLNG~ 2, Iuus JCM, BACH M-A: Re~stricted T-cell Receptor VB Gene by Myelin Basic Protein-
Specilic T-cell Clones in Multiple ScIerosis: Predominant Genes Vary in ImEviduais. Pnx NaU Acad Sci USA 1991, 88:2466-2470. Reports the dominance of VP15 gene in T-cell clones derived from one poiyclonal MS-derived ~anti-MBP T-cell Une recognizing sequence 149-162. Also documents a PCR study of TCR rearrangement patterns.
900
Autoimmunity 17. .
C HOU YK, HENDERIK~ P. VAINIE~% M, WH~THA&I R, BOURDETIF D, CHOU CH-J, ~-LUHIM G, OFFMR H, VANDENBAR~; fi Specificity of Human T Cell Clones Reactive to Immunodominant Epitopes of MyeUn Basic Protein. / Neuracii Res 1991. 28:28&290. Reports VP5 usage in four out of eight T-cell clones (different target epiropes) derived from one MBP-specific T-cell line from an MS parienr (HLA-DR2). Also document? TCR typing using a monoclonal antibody.
terminant on MyeUn and Oligodendrocytes, and Augments Demyelination in Experimental Allergic Encephalomyelitis. J &.\p Med 1990, 171:18931908. Repons BALB/c mouse-derived monoclonal antibodies recognizing both TMEV and galactoscerebroside epiropes. The monoclonal antibody binds to MBP-expressing oligodendroc)qes hf chq and to myelin in brain sections. When injected into a mouse with EAE. it causes demyeelination.
18. .
31. .
WUCHERPWNNlC KW, WEtNER HL, HAFLER DA: T-cell Recognition of Myelin Basic Protein. fmmunol To@ 1 9 9 1 , 12~277-282. Discussion of MBP as an autoantigen in MS, and summary of epirope recognition and TCR gene usage by MS-derived T-cell clones, 19. .
OK~ENBERC JR, STUART S, BEGOXH AB, BELL RB, ERLICH kh STElNhlAN L, BEMARD CCA: Limited Heterogeneity of Rearranged T-cell Receptor Vu Transcripts in Brains of Multiple sclerosis Patients. Nature 1990, 345~344-346. PCR amplification of Vu gene transcripts from MS autopsy brains. Preferential ampIification of Vp12.1. 20.
YAMM~URA T, NAMIKA%~A T , ENDOW M, KUNISHITA T. TABIRA T: Passive Transfer of Experimental Allergic Encephalomyelitis Induced by ProteoUpid Apoprotein. J Neural Sci 1986, 76:269-275.
21.
SATO J, S%u K. ENWH M, KoltcE F, KLIN~SHITA T. N~UKAWA T , T~URA T , TABIRA T: Experimental Allergic Encephalomyelitis Mediated by Murine Encephalitogenic T Cell Limes SpecUic for Myelin ProteoUpid Apolipoprotein J Immunol 1987, 138:179-184.
22.
-i-UOHY WC, LU ZJ, SoBEl. RA, ~URSEN RA, LEES MB: A Synthetic Peptide from Myelin Proteolipid Protein Induces Experimental AUergic Encephalomyelitis. J fmmunol 1988, 141:1126-1130.
WHITHAM RH, BOURD~E DN, HASHIM GA, HERNDON GM, ILG RC, VANDENBARK AA, OFFNER H: Lymphocytes Tom SJL/J Mice Immunized with Spinal Cord Respond Selectively to a Peptide of ProteoUpid Protein and Transfer Relapsing Demyelinating Experimental Autoimmune Encephalomyelitis. ~_ J Immunol 1991. 146:101-107. T cells from spinal cord immunized SJVJ mice with EAE preferentially respond to PLP (synthetic peptides 139151 and 141-151) rather than to MBP epitopes. PLP may be the dominant encephalitogen in SJUJ mice. 23. . .
24.
KEENEDY MK, T A N L - J , DA L C A N T O M, Tuo~v V , L u Z , TROTTER JL, MILLER SD: Inhibition of Murine Relapsing Experimental Autoimmune Encephalomyetitis by Immune Tolerence to Proteolipid Protein and its Encephalitogenic Peptides. J Immunol 1990, 144909-915.
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34. .
BOYWI’ KB, TAKAHASHI N, PAT-Y DB, .%DO~NNIK AD, DIAMOND M. HOOD I+ PRLISINER SB: DNA Length Polymorphism 5’ to the MyeUn Basic Protein Gene is Associated with Multiple Sclerosis. Ann Nerrrol 1990, 271291-297. Ten alleles identified in the lirsr human MBP exon on chromosome 18. Increased occurrence of certain alleles in MS patients. This is an RFLP Study.
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HILIXRT J, &NC C, OLERUP 0: No Association with Germline T CeU Receptor J3 Chain AIIeles or Haplotypes in Swedish Patients with Multiple Sclerosis. J Neuroimmunol 1991, 31:141-147. RFLP analaysis of 100 MS patients (23 chronic progressive, 77 relapsing/remitting). No association with allelk pattern or TcR P.chain gene haplotypes is reported. 36.
MARCADET A, GEBUHRER L, BETUEL H, SEIGNALET J, FREIDEL AC, CONFAVREUX C , BILLIARD M DAU~~ER J, C OHEN D: DNA Poly morphism Related to HLA-DR2 Dw2 in Patients with Narcolepsy. lmmunogen 1985, 22:67‘+683.
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MIGNOT E, W A N G C , RATIXXI C , GAISER C , Lovzrr M , GU1UMINALJI.T C, DEMENT W C , GRUMET FC: Genetic Linkage of Autosomal Recessive Canine Narcolepsy with a p Immunoglobulin Heavy Chain Switch-like Segment. PI-CC Natf Acad Sci LX4 1991, 88:3475-3478. Restriction fragment length polymorphism mapping of a canine narcolepsy-associated gene to immunoglobulin nearly chain switch gene; no association with MHC class II, as in human narcolepsy. 39. .
O~SSON T, ZHI WW, HOJEBERG 8, Kosrul~s V, Yu-Pmc J, ANDERSON G, EKRE H-P, LINK H: Autoreactive T Lymphocytes Secretion of Interferon-y. J Clin Invest 1990, 86:981-985. Demonstration of activated, cytokine-secreting T cells in CNS of MS patients using an ‘immunospot’ technique. 40. .
SE~MAJ K, RAWE CS, CANNEUA B, BROSNAN CF: Identilication of Lymphotoxin and Tumor Necrosis Factor in Multiple Sclerosis Lesions. J Clin Invest 1991, 87:949-954. lmmunocytochemical visualization of TNF-a and TNF-j3 in MS brain sections. TNF-a is mainly associated with astrocytes and macrophages, and with some endothelia of active lesions. TNQ is found on CD3 T ceUs and microglia cells. 41. . .
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Rapid induction of NGF expression in astrocyte cultures and in situ by IL-l. Autocrine induction of IL-1 synthesis in CNS. The study was carried out using in tiiu hybridization and northern blot analysis techniques. B ROWN MC, PERRY VH, LUNN ER, GORDON S, HELIW R: Macrophage Dependence of Peripheral Sensory Nerve Regeneration: Possible Involvement of Nerve Growth Factor. Neuron 1991, 6359-370. Reports that WaIlerian degeneration in C57~uOla mutant mice is slow, and associated with a relative lack of inhltrating macrophages. Expres sion of nerve growth factor (NGF) and NGF receptor mRNA is also reported to be abnormally low. 47. .
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Levels in the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis. J Neuraimmrcnol 1991, 3267-65. IL.~ and TNF-a titers are elevated in the CSF of MS patients. but also in other inUa.mmatory CNS diseases. No correlation with oligoclonal immunoglobulins in CSF is reported.
diseases Wekerle 901
LAsshwNN
H, ROWER K, Zthl~%~c~ F, V.&z& K: Expression of Adhesion Molecules and Histocompatibility Antigens at the Blood-Brain Barrier. Brain Pafbol 1991, 1:115-123. Excellent raiew of in situ expression of cell adhesion molecules, including members of the immunoglobulin gene superfamily. 52. .
RA, MI T CHELL ME, FONDREN G: Intercellular Adhesion Molecule-l (ICAM-1) in Cellular Immune Reactions in the Central Nervous System. Am J Pafhf 1990, 136:1309-1316. Strong expression of CAM in MS lesions. Intercellular adhesion molecule (ICAM)-l is on membranes of microvessel, some glia cells, and infiltrate cells. In contrast, the ICAM. @and lymphocyte function. associated antigen-l is expressed solely on mononuclear ceUs. 53. .
SOBEL
CF, RAUW CS: Hypotbesis: Antigen-specific T CeUs Prime Central Nervous System Endothelium for Recruitment of Nonspecific I&lammatory Cells to Effect AutoImmune DemyeIination. J New roimmunol 1991, 33:237-244. On the basis of the author’s own morphological work it is suggested that antigen-specific T cells prime CNS endothelium for recruitment of nonspecific intlammatory cells to effect autoimmune demyelination.
54. .
CROSS AH, CANNEUA B, BROSNAN
55. OSBORN L Leukocyte Adhesion to Endothelium In InIlam. mation. Cell 1990, 62:2&6. Useful introduction to human ceU adhesion molecules involved in rectuitment of inUammatory cells into tissue lesions. DANA N. FATWUMH DM, ARNAOUT MA Expression of a Soluble and Functional Form of the Human 02 Integrin CDIlWCDlS. Proc Nat1 Acad Sci USA 1991, 88:310&3110. Reports engineering of integrin genes, which may lead to therapeutic manipulation of ir&tmmatory ceU recirculation. 56. .
H Wekerle, Max-Planck Institute for Psychiatry, Klopferspitz 18, D-8033, Martinsreid, Munich, Germany.