Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Identification of autoantibodies associated with myelin damage in multiple sclerosis

Nature Medicine volume 5, pages 170–175 (1999)Cite this article

Abstract

The molecular mechanisms underlying myelin sheath destruction in multiple sclerosis lesions remain unresolved. With immunogold–labeled peptides of myelin antigens and high–resolution microscopy, techniques that can detect antigen–specific antibodies in situ, we have identified autoantibodies specific for the central nervous system myelin antigen myelin/oligodendrocyte glycoprotein. These autoantibodies were specifically bound to disintegrating myelin around axons in lesions of acute multiple sclerosis and the marmoset model of allergic encephalomyelitis. These findings represent direct evidence that autoantibodies against a specific myelin protein mediate target membrane damage in central nervous system demyelinating disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Electron micrographs of myelin pathology in marmoset EAE and human MS.
Figure 2: Identification of autoantibodies within marmoset EAE lesions with gold–labeled conjugates.
Figure 3: Staining of normal–appearing white matter with gold–labeled conjugates.
Figure 4: Identification of autoantibodies within MS brain tissue from the subject in Fig. 1c.

Similar content being viewed by others

References

  1. Brosnan, C.F. & Raine, C.S. Mechanisms of immune injury in multiple sclerosis. Brain Pathol. 6, 243– 257 (1996).

    Article  CAS  Google Scholar 

  2. Hohlfeld, R. Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120, 865–916 (1997).

    Article  Google Scholar 

  3. Wekerle, H., Linington, C., Lassmann, H. & Meyermann, R. Cellular immune reactivity within the CNS. Trends Neurosci. 9, 271–277 (1986).

    Article  Google Scholar 

  4. Willenborg, D.O. & Prowse, S.J. Immunoglobulin–deficient rats fail to develop experimental allergic encephalomyelitis. J. Neuroimmunol. 5, 99–109 (1983).

    Article  CAS  Google Scholar 

  5. Piddlesden, S.J., Lassmann, H., Zimprich, F., Morgan, B.P. & Linington, C. The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am. J. Pathol. 143, 555–564 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wolf, S., Dittel, B., Hardardottir, F. & Janeway, C.J. Experimental autoimmune encephalomyelitis induction in genetically B cell–deficient mice. J. Exp. Med. 184, 2271– 2278 (1996).

    Article  CAS  Google Scholar 

  7. Raine, C.S. & Bornstein, M.B. Experimental allergic encephalomyelitis: an ultrastructural study of demyelination in vitro. J. Neuropathol. Exp. Neurol. 29, 177–191 (1970).

    Article  CAS  Google Scholar 

  8. Raine, C.S., Hummelgard, A., Swanson, E. & Bornstein, M.B. Multiple sclerosis: serum–induced demyelination in vitro. A light and electron microscope study. J. Neurol. Sci. 20, 127–148 (1973).

    Article  CAS  Google Scholar 

  9. Genain, C.P. et al. Antibody facilitation of multiple sclerosis–like lesions in a non human primate. J. Clin. Invest. 96, 2966–2974 (1995).

    Article  CAS  Google Scholar 

  10. Kirschner, D.A. & Blaurock, A.E. in Myelin: Biology and Chemistry (ed. Martenson, R.E.) 3– 78 (CRC, Boca Raton, Florida, 1992).

    Google Scholar 

  11. Brunner, C., H. Lassman, Waehneldt, T.V., Matthieu, J.M. & Linington, C. Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2'3' cyclic nucleotide phosphodiesterase in the CNS of adult rats. J. Neurochem. 52, 296–304 (1989).

    Article  CAS  Google Scholar 

  12. Lassmann, H., Brunner, C., Bradl, M. & Linington, C. Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol. (Berl) 75, 566–576 (1988).

    Article  CAS  Google Scholar 

  13. Takisawa, T. & Robinson, J.M. Use of 1.4–nm immunogold particles for immunocytochemistry on ultra–thin–cryo–sections. J. Histochem. Cytochem. 43, 1615– 1623 (1994).

    Article  Google Scholar 

  14. Genain, C.P. et al. Late complications of immune deviation therapy in a non human primate. Science 274, 2054– 2057 (1996).

    Article  CAS  Google Scholar 

  15. Tabira, T. & Kira, J.–I. in Myelin: Biology and Chemistry (ed. Martenson, R.E.) 783–799 (CRC, Boca Raton, Florida, 1992).

    Google Scholar 

  16. Warren, K.G., Catz, I. & Steinman, L. Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B cell epitope and a model of its features. Proc. Natl. Acad. Sci. USA 92, 11061–11065 (1995).

    Article  CAS  Google Scholar 

  17. Raine, C.S., Snyder, D.H., Valsamis, M.P. & Stone, S.H. Chronic experimental allergic encephalomyelitis in inbred guinea pigs. An ultrastructural study. Lab. Invest. 31, 369–380 (1974).

    CAS  PubMed  Google Scholar 

  18. Dal Canto, M.C., Wisniewski, H.M., Johnson, A.B., Brostoff, S.W. & Raine, C.S. Vesicular disruption of myelin in autoimmune demyelination. J. Neurol. Sci. 24, 313–319 (1975).

    Article  CAS  Google Scholar 

  19. Seil, F.J., Falk, G.A., Kies, M.W. & Alvord, E.C. The in vitro demyelinating activity of sera from guinea pigs sensitized with whole CNS and with purified encephalitogen. Exp. Neurol. 22, 545–555 (1968).

    Article  CAS  Google Scholar 

  20. Raine, C.S., Johnson, A.B., Marcus, D.M., Suzuki, A. & Bornstein, M.B. Demyelination in vitro. Absorption studies demonstrate that galactocerebroside is a major target. J. Neurol. Sci. 52, 117– 131 (1981).

    Article  CAS  Google Scholar 

  21. Brosnan, C.F., Traugott, U. & Raine, C.S. Analysis of humoral and cellular events and the role of lipid haptens during CNS demyelination. Acta Neuropathol. (Berlin) Suppl. 9, 59–70 (1983).

    Article  CAS  Google Scholar 

  22. Linington, C. & Lassmann, H. Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG). J. Neuroimmunol. 17, 61– 69 (1987).

    Article  CAS  Google Scholar 

  23. Gerritse, K. et al. The involvement of specific anti myelin basic protein antibody–forming cells in multiple sclerosis immunopathology. J. Neuroimmunol. 49, 153–159 (1994).

    Article  CAS  Google Scholar 

  24. Sun, J. et al. T and B cell responses to myelin oligodendrocyte glycoprotein in multiple sclerosis. J. Immunol. 146, 1490–1495 (1991).

    CAS  PubMed  Google Scholar 

  25. Benveniste, E.N. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. 75, 165– 173 (1997).

    Article  CAS  Google Scholar 

  26. Morris, G. in Epitope mapping protocols 1–416 (Humana Press, Totowa, 1996).

    Book  Google Scholar 

  27. Amor, S. et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J. Immunol. 153, 4349– 4356 (1994).

    CAS  Google Scholar 

  28. Ichikawa, M., Johns, T.G., Liu, J. & Bernard, C.C.A. Analysis of the fine B–cell specificity during the chronic/relapsing course of a multiple sclerosis–like disease in Lewis rats injected with the encephalitogenic myelin oligodendrocyte glycoprotein peptide 35–55. J. Immunol 157, 919–926 (1996).

    CAS  PubMed  Google Scholar 

  29. Lassmann, H., Raine, C.S., Antel, J. & Prineas, J. Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J. Neuroimmunol. 86, 213–217 (1998).

    Article  CAS  Google Scholar 

  30. Aleu, F.P., Katzman, R. & Terry, R.D. Fine structure and electrolyte analysis of cerebral edema induced by alkyl–tin intoxication. J. Neuropath. Exp. Neurology 22, 403– (1963).

    Article  CAS  Google Scholar 

  31. Compston, A., Scolding, N., Wren, D. & Noble, M. The pathogenesis of demyelinating disease: insights from cell biology. Trends Neurosci. 14, 175–182 (1991).

    Article  CAS  Google Scholar 

  32. Prineas, J.W. & Connell, F. The fine structure of chronically active multiple sclerosis plaques. Neurology 28, 68–75 (1978).

    Article  CAS  Google Scholar 

  33. Epstein, L.G., Prineas, J.W. & Raine, C.S. Attachment of myelin to coated pits on macrophages in experimental allergic encephalomyelitis. J. Neurol. Sci. 61, 341–348 (1983).

    Article  CAS  Google Scholar 

  34. Moore, G.R.W. & Raine, C.S. Immunogold localization and analysis of IgG during immune–mediated demyelination. Lab. Invest. 59, 641–648 (1988).

    CAS  PubMed  Google Scholar 

  35. Pham–Dinh, D. et al. Characterization and expression of the cDNA coding for the human myelin/oligodendrocyte glycoprotein. J. Neurochem. 63, 2353–2356 (1994).

    Article  Google Scholar 

Download references

Acknowledgements

We thank E.P. Reich (Anergen, Redwood City, California) for the gift of MSA peptide, and E. Swanson, M. Pakingan and H. Finch for technical assistance. This work was supported by grants from the National Institutes of Health (NS 08952, NS 11920 to C.S.R.; AI 43073 to S.L.H.), the National Multiple Sclerosis Society (RG 1001–I–9 to C.S.R.), and the Nancy Davis Center Without Walls. C.P.G. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society.

Author information

Authors and Affiliations

  1. Department of Neurology, University of California, San Francisco, 94143–0435, California, USA

    Claude P. Genain & Stephen L. Hauser

  2. Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, 10461–1602, New York, USA

    Barbara Cannella & Cedric S. Raine

Authors
  1. Claude P. Genain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Cannella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen L. Hauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cedric S. Raine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claude P. Genain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Genain, C., Cannella, B., Hauser, S. et al. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5, 170–175 (1999). https://doi.org/10.1038/5532

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/5532

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing