The pathogenetic significance of cross reactions in autoimmune disease of the nervous system

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N e w directions i n research

The, pa

ogenetic significance of cross reactions in autoimmune disease of the nervous system

Today's thinking about many diseases - multiple sclerosis, myasthenia gravis, insulin-dependent diabetes, and rheumatoid arthritis are well known examples - is dominated by the theory of autoimmunity. Prima facie evidence in favor of this theory is the demonstration, in a given disease, that patients make antibody or immune T lymphocytes specific for a significant component of the target tissue and that the level of such antibody (or T cells) is correlated in time and extent with the disease process. The theory is bolstered by the existence of suitable animal models in each case and by serum or cell transfer experiments where these are possible. Three types of immunologic cross reactions involving putative autoantigens claim our attention: those between an autoantigen and an exogenous agent, usually bacterial or viral; those between an autoantigen, e.g. of nervous tissue, and another tissue element such as tumor; and those between an autoantigen of nervous tissue and a membrane component of immunologically active lymphoid cells. In each case, one must ask three quite different questions. What role does the cross-reaction have in the induction of autoimmunization? Does the cross-reaction have direct pathogenetic implications in the production of lesions? Are there indirect pathogenetic consequences of the cross-reaction, affecting, for example, immune regulation? This review was undertaken because of the numerous recent reports that monoclonal IgM with apparent specificity for myelin-associated glycoprotein (MAG), found in some patients with plasma cell neoplasms (Waldenstr6m's macroglobulinemia), is associated with a demyelinating disease of the peripheral nervous system~-4; that MAG is lost in the demyelinatinglesions of acute multiple sclerosis (MS) earlier and to a greater extent than the better known myelin basic protein (MBP)5'6; that an antigen cross-reactive with M A G is present on natural killer (NK) cells3'*'7'8;and that NK cells are severely depressed in many patients with multiple sclerosis 7'9'1°.These findings provide a convenient test of the questions listed above and will serve here to introduce a broader discussion of immunologic cross-reactions specifically related to MS and other demyelinative diseases. (Recent general reviews of immunologic findings in MS are presented in Refs 11-13.) The immunogenie component of MAG, in the neuropathy studies cited above, appears to be carbohydratC, as is also implied by the fact that the response is IgM. Since the neuropathy frequently precedes the neoplasm, it appears to be associated with polyclonal antibody formed in response to an unknown, presumably bacterial antigen. The frequency of the neoplasm, then, and the frequency of the neuropathy both may simply reflect the frequency with which this polyclonal response occurs. On the other hand, since antibody reactive with M A G cross© 1984, Elsevier Science Publishers B.V., Amsterdam 0167 - 4919/84/$02.00

reacts with gangliosides , the effector phase which result s in neuropathy may involve ganglioside bound to any of several myelin proteins 4. It is difficult to find a comparable explanation for the precocious breakdown of M A G in the brain lesions of multiple sclerosis 5'6 because anti-MAG antibody is not prominent in this disease. This particular finding may have an entirely unrelated cause, such as the unusual sensitivity of M A G to endogenous proteases 1~. The low level of N K cells in many MS patients 7'9'1°has been attributed to a possible reaction with anti-MAG antibody 3'7and related to the additional presence of lymphocytotoxic antibody1~-17. Again an unrelated finding provides a more probable explanation: prostaglandins of the E series, released by activated monocytes in the patients' circulation, modulate the surface membrane of NK cells so that they lose both the characteristic phenotypic marker and their cytotoxic activity18'~9.The possible effect of such NK-cell loss on immune regulation and lesion formation in a chronic, sometimes remitting disease like MS remains conjectural at the present time. There is an interesting parallel between the questions which surround the possible role of M A G in MS and questions about the role of the unrelated T8 marker. T8 is present on both cytotoxic and suppressor T lymphocytes and on cultured ovine oligodendrocytes, the cells which make and maintain myelin 2°. T8 + cells disappear from the circulation of patients with active disease, and the suggestion has been made that antibody to T8 may produce both this cell loss and the demyelination 21. Again the modulation of T8 by prostaglandins 18'19provides a more facile explanation of the disappearing T8 + cells in the blood. It is widely felt, nevertheless, that the temporary disappearance ofT8 + cells may play an important role in the protracted and remitting character of MS but this has not really been established. In MS, most of the emphasis in recent studies has been on possible immune responses against protein antigens of myelin such as proteolipid and, in particular, myelin basic protein (MBP). Epidemiologic studies suggest strongly that the initial immunizing event involves infection with common childhood viruses rather than bacteria, and neuropathologic studies place the major emphasis on cell-mediated immunity rather than the action of antibody as the major pathogenetic mechanism of this disease (reviewed in Refs 11-13). Crossimmunization by viral infection is most easily explained (Table 1) by tissue damage which result from viral invasion of the nervous system, and releases immunogenic antigen. However, there may also be chemical homology (and immunologic cross-reactivity) between viral and tissue antigens; homologous peptide sequences have now been demonstrated, for example, in measles P-protein and MBP 22. A more complex form of

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TABLE I Possible mechanisms of cross-immunization to myelin antigens by virus infection Virus damages white matter, releases myelin antigen Virus antigen cross reacts with myelin antigen Anti-idiotype against antiviral antibody reacts with viral receptor on myelin Myelin antigen is incorporated in viral envelope? (Myxo, paramyxo, pox, and herpes viruses) Virus activates cells (endothelium, macrophages, glia) and increases cellular Ia antigens: enhances presentation of myelin antigen(s) to specific effector cells Systemic immune reaction to virus releases lymphokines which activate cells and increase cellular Ia and presentation of myelin antigen(s) Modified from Ref. 46.

cross-reactivity is seen in the case of antibody reactive with tissue components which serve as viral receptors: such antibody may actually be directed against idiotypic sequences in antiviral antibody2L An entirely different mechanism of cross-immunization is implied by the occurrence ofT-cell sensitization to MBP in human subjects infected with a variety of enveloped viruses 24 and the finding that white matter in which virus has grown shows greatly enhanced immunogenicity 25. Here the critical element in immunization may be the juxtaposition of viral and tissue antigens in the viral envelope. Another alternative is that immunization may be enhanced by the appearance or increased concentration of Ia antigens ( H L A D R in man) at the surface of endothelial cells 26'27 or of monocytes 27 or astrocytes 28, when these are activated, either by direct virus infection or by lymphokines released as part of the systemic reaction to virus 29. It has been suggested that the population of responding T lymphocytes increases with increased density of Ia on antigen-presenting cellsS°: this, then, would intensify both immunization and the elicitation event in autoimmune disease. It should be noted that where cross-immunization involves a bacterial component and a neural antigen, as in the case of MAG, the evidence suggests strongly that true immunologic cross-reactivity, based on chemical homology, usually plays the major role 31'32. The study of these questions from the standpoint of cell-mediated immunity is more technically demanding than the study of antibody and is only now coming into its own. T-cell sensitization to MBP has been demonstrated in dogs in which demyelinative lesions develop after infection with canine distemper virus 33 and in rats with similar lesions after infection w i t h J H M virus (MHV-4) 34 The latter disease could be transferred by transfer of cells free of virus. The corresponding observation in human subjects is the appearance ofT-cell reactivity to MBP in a high proportion of individuals with postinfectious encephalomyelitis following measles, varicella, or rubella infection 24. Curiously, despite many positive reports, the presence of such MBP-reactive T-cells in MS has not been conclusively demonstrated. Such study is made easier by the use of techniques for immortalizing T and B lymphocytes 35, notably cloning in the presence of growth factors, hybridoma• formation, viral transformation, or the use of spontaneous neoplasms of lymphoid cells. Hybridoma technology was used to

study the range of autoantibody responses in mice infected with reovirus type I; these included antibody against pituitary, pancreatic islets, gastric mucosa, and nuclei, and also against specific hormones such as insulin, glucagon, and growth hormones 36. T-cell lines and clones have been used to study acute and chronic relapsing EAE 37'~8but have not yet been applied to models ofvirally induced autoimmunization. Again a variety of attempts are underway to clone T cells from human subjects. In a representative recent study 39, T lymphocytes reactive with measles virus and also with MBP were cloned from the cerebrospinal fluid of MS patients. Receptors for neurotransmitters, which can serve as antigens, are increasingly well understood. The prototype is the acetylcholine receptor, the target of immune attack in myasthenia gravis. This and receptors for opioids, dopamine, catecholamines, prostaglandins, neuropeptides, and macromolecules like interferon are found not only on neural elements but also on lymphocytes and, in some instances, on vascular endothelium, mast cells, basophils, or other cells which play a significant effector or regulatory role in immunologically mediated disease 4°'41(see Ref. 42). The initial immunization, in the case of aeetylcholine receptor, appears to involve common organisms of the gastrointestinal flora ~2. In Sydenham's chorea, a streptococcal cell membrane carbohydrate antigen is involved ~1. The effect of antibody in each case is functional, reducing responsiveness of the target cells in the one case and stimulating it in the other. In the paraneoplastic syndromes 4~, tumors serve as immunizing agents. These appear to involve a different class of neuronal membrane antigens and the effect of antibody (or immune T cells) is often to destroy the targetcell population rather than to induce functional change. Well-studied examples include the Purkinje cells, which are lost in progressive cerebellar degeneration, and the large ganglion cells of the retina in autoimmune blindness 44. A variety of other target populations may be involved. There appears to be little or no cross-reactivity between this class of antigens and lymphocyte membrane components. Thus immunoregulatory involvement in these disease processes appears to be minimal. The application of modern techniques of molecular and cell biology to the analysis of autoimmune diseases in the nervous system promises rapid identification of the responsible antigens and elucidation of the mechanisms of immunization and lesion formation. [~] BYRON H. W A K S M A N National Multiple Sderosis Society, New York, New York 10017, U.S.A.

References 1 Latov, N., Sherman, W. H., Nemni, R. etal. (1980) NewEnglandJ. Med. 303, 618-621 2 Braun, P. E., Frail, D. E. and Latov, N. (1982)J. Neurochem. 39, 1261-1265 3 Murray, N. and Steck, A. J. (1984) Lancet i, 711-713 4 Nobile-Orazio, E., Hays, A. P., Latov, N. et al. (1984) Neurolog~Suppl. I, 256. Abstr. 5 Itoyama, Y., Stemberger, N. H., Webster, H. DeF. et al. (1980)Annals Neurol. 7, 167-177 6 Gendelman, H. E., Pezeshkpour, G. H., Wolinsky, J. S. et al. (1984) Neurol. suppl. I, 257. Abstr. 7 SchuHer-Petrovic, S., Gebhart, W., Lassmann, H. et al. (1983) Nature (London) 306, 179-181

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348 8 McGarry, R. C., Helfand, S. L., Quarles, R. H. a at (1983) Nature (London) 306, 376-378 9 Benczur, M., Petrlfnyi, C. G., PAlffy, G. etal. (1980) Clin. Exp. lmmunoL 39, 657-662 10 Neighbour, P. A., Grayzel, A. I. and Miller, A. E. (1982) Clin. Exp. lmmunol. 49, 11-21 11 MeFarlin, D. E. and McFarland, H. F. (1982) New EnglandJ. Med. 307, 1183-1188; 1246-1251 12 Antel, J. P., ed. (1983) NeurologgeClini~xvol. I, no. 2, W. B. Saunders CO., Philadelphia 13 Waksman, B. H. and Reynolds, W. E. (1984) Proc. Soc. Exp. Biol. Med. 175, 282-294 14 Sato, S., Quarles, R. H. and Brady, R. O. (1982)J. Neuroehem. 39, 97-105 15 Kuwert, E. and Bertrans, J. (1972) Eur. Neurol. 7, 65 16 Weiner, H, L. and 8ehocket, A. L. (1979) Neurolog~29, 1504-1508 17 Tsokamoto, T., Ebina, T., Takase, S. etal. (1982) TohokuJ. Exp. Med. 136, 121-128 18 Dore-Duffy, P. and Zurier, R. B. (1981) Clin. Immunol. Inmmnopath. 19, 303-313 19 Merrill, J. E., Gerner, R. H., Myers, L. W. eta/. (1983) J. Neuroimmunol. 4, 223-237; 239-251 20 Oger, J. J-F., Szuchet, S., Antel, j. a d (1982) Nature (London) 295, 66-68 21 Antel, J., Oger, J. J-F., Jaekevicius, S. a al. (1982) Pr0¢. NatlAcad. Sd. USA 79, 3330-3334 22 Fujinami, R. S. and Oldstone, M. B. A. Unpublished results 23 Nepom, J. T., Weiner, H. L., Diehter, M. A. stal. (1982),]. Exp. Med. 155, 155-167 24 Johnson, R. T., Griffin, D. E., Hirsch, R. L, aal. (1984) New Eng/and J. Med. 310, 137-141 25 Van Alstyne, D., Dyck, I. M., Berry, K. etal. (1983) Neuro/o~, 33, Suppl. 2, 195, Abstr. 26 Suckling, A. J., Pathak, S., Jagelman, S. etal. (1978)J. Neurol. Sdmwes 39, 147-154 27 Sobel, R. A., Blanchette, B. W., Bhan, A. K. etal. (1984),]. Immunol.

132, 2392-2401; 2042-2407 28 Fierz, W., Fontana, A. and Wekerle, H. (1984) Neurolog~34, 257. Abstr. 29 Neta, R., Salvin, S. B. and Sabaaw, M. (1981) Cell. Immunol. 64, 203-219 30 Bevan, M. J. (1984) Immunol. Today 5, 128-130 31 Husby, G., van de Rijn, I., Zabriskie, J. L. etal. (1976)J. Exp. Med. 144, 1094-1110 32 Stefansson, K., Dieperink, M. E., Richman, D. P. and Marton, L. S. (1984) Abstr. Soc. Neurosa, 14th Annual Meeting, Anaheim, p. 291. 33 Cerruti-Sola, S., Kristensen, F., Vandevelde, M. a al. (1983)J. Neuroimmunol. 4, 77-90 34 Watanabe, R,, Wege, H. and ter Meulen, V. (1983)Nature(London)305, t50-153 35 Waksman, B. H. (1983)Annals Neurol. 13, 587-591 36 Haspel, M. V., Onadera, T., Prabhakar, B. S. etal. (1983)Science 220, 304-306 37 Ben-Nun, A., Wekerle, H. and Cohen, I. R. (1981) Eur.J. lmmunol. 11, 195-199 38 Mokhtarian, F., MeFarlln, D. E. and Rains, C. S. (1984) Nature (London) 309, 354-358 39 Richert, J. R., McFarland, H. F., McFarlin, D. E. etal. (1983) Prof. Nail Aead. S,:i. USA 80, 555-559 40 Fuehs, S., Sehmidt-Hopfeld, I., Tridents, G. etal. (1980) Nature(London) 287, 162-164 41 Richman, D. P. and Amason, B. G. W. (1979) Pro~. NatlAcad. Sd. USA 76, 4632-4635 42 Goetzl, E.J., Blalock, J. E. and Feldman, J. eds. (t985)Conference on Neuromodulation of Immunity and Hypersensitivity J. Immunol. (in press) 43 Stefansson, K. and Arnason, B. G. W. (1984) in ComprehensiveT~'tbookof Onco/ogy(Moosa, A. R., Robson, M. C. and Schirupff, S. G., (eds), Williams and Wilkins, Baltimore (in press) 44 Kornguth, S. E., Klein, R., Appen, R. aal. (1982) Career50, 1289-1293 45 Johnson, R. T. (1983) in Vimm and Dtm~linating Disuses (C. A. Mires, M. L. Cuzner and R. E. Kelly, eds), pp. 7-19, Academic Press, New York

High connectivity within the network? In the ten year period following the twin revelations of M H C restriction and the idiotypic network, which led to the demise of horror autotoxicus, many of the far-reaching implications of M H C restriction have been fully validated andJerne's enlightening and encompassing view into the 'web of V domains' has proven amazingly prescient. Despite this, at both the T- and B-cell levels, we are still at the dawn of understanding the influences that are paramount in establishing the constitution of the mature immune repertoire. It is commonly granted that T-cell recognition is self-referential and chimera experiments have shown that each individual learns which M H C and Igh entities it will regard as self. In addition, the M H C molecules serve as part of an overall sign (semiotic") system whose rules govern intracellular communication, directing T-cell interactions into appropriate and unambiguous channels. We may also arbitrarily divide idiotypic affairs into their self-referential and semiotic aspects. Some students of the network consider that it is an autonomous whole, coordinating the activities of its members and embodying the whole organism. It is one of the engaging dualities of the immune system that its overall plan exploits the recognition of its own receptors, while these receptors concurrently play a decisive role in addressing the external world. It has been difficult to establish the balance between the autonomous aspects of the network and ks semiotic function of providing signs for intercellular recognition, especially between T-cell ~Semiotics is the study of signs and codes ~. Following Tada 3, 'immunosemiotics' can be defined as the study of the signs used in communication between immunologically active cells. © 1984,ElsevierSciencePublishersB.V.,Amsterdam 0167- 4919/84/$02.00

subpopulations, or between T and B cells. One recent idea in accord with this aim has been that certain 'regulatory idiotopes' 4 are different from others in serving as recognition sites for T cells, uniting T regulatory circuitry with the B receptor idiotypic universe. Predominant idiotypes, in part, result from such an organization, ensuring regulatory simplicity: instead of an idiotypic Tower of Babel, cells can speak to each other in a few key languages. In a fascinating recent report, Antonio Coutinho and his colleagues 5 have addressed an important issue which may relate to both the autonomous and coordinative aspects of the network: does the system start out as a network in ontogeny, in the absence of external antigenic stimuli? An essential property of such a formal network would be connectance among its members. As the repertoire expands, although each new receptor specificity might fit somewhere within the web of V domains, connectance - defined as the chance that any two idiotopes would interact with each other - must decrease. Therefore, Holmberg e t a l . 5 focused on the normal neonatal repertoire, expecting to detect the highest connectance at that time, their underlying assumption being that this would result from the stimulatory interplay of idiotype and anti-idiotype within the network. They have studied the reactivity between IgM molecules, presumably owing to their complementary V regions: a group of 70 from a collection of 112 monoclonal (Mab) IgM preparations from four 6-day old littermates were distributed in the solid phase a n d reacted with 9 Mab from the collection, each of which had been conjugated to