Autoimmune Responses to the Myelin Oligodendrocyte Glycoprotein (MOG) in the Pathogenesis of Inflammatory Demyelinating Diseases of the Central Nervous System

  • Christopher Linington
  • Martin Adelmann
  • Roxana Popovici
Part of the NATO ASI Series book series (NSSA, volume 258)


A T cell mediated autoimmune response is believed to trigger the characteristic inflammatory demyelinating pathology of multiple sclerosis (MS)1 . However the immune effector mechanisms responsible for the selective loss of myelin in MS have still to be defined. Several authors have suggested that demyelination in MS is simply a consequence of the local inflammatory response in the CNS, “bystander demyelination”. In vitro studies demonstrating that oligodendrocytes and myelin are highly susceptible to damage by a wide variety agents released by monocytes and T cells during an inflammatory response 2,3. However, ultrastructural and immunocytochemical studies indicate that primary demyelination in MS may be mediated by a specific humoral response directed against the myelin membrane. Electron microscopy reveals that macrophages attack, phagocytose and degrade apparently normal myelin in MS 4, introducing processes between myelin lamellae and actively stripping sheets of membrane from the myelin sheath, which is then phagocytosed by a process resembling receptor mediated endocytosis. Interestingly the phagocytosis of myelin is closely associated with the capping of IgG on the macrophage surface suggesting that a specific receptor/ligand interaction is involved in this process5. The ligands involved in this interaction are unknown, but possible candidates are immunoglobulin or complement activation products (C3bi) deposited on the myelin surface. In MS there is certainly ample indirect evidence for the activation of complement on myelin surface, in particular, the intrathecal consumption of complement 6 and the presence of myelin membrane fragments coated with terminal complement complexes the cerebrospinal fluid 7. The deposition of terminal complement components and immunoglobulins can also be demonstrated in MS lesions8,9. However, as yet no myelin-specific autoantibody response has been identified that can account for the observed intrathecal activation of complement in MS.


Multiple Sclerosis Myelin Basic Protein Autoimmune Response Experimental Allergic Encephalomyelitis Myelin Oligodendrocyte Glycoprotein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Martin, R., McFarland, H.F. and McFarlin, D.E. Immunological aspects of demyelinating diseases. Annu. Rev.Immunol. 10: 153–187, 1992.PubMedCrossRefGoogle Scholar
  2. 2.
    Lyman, W.D., Roth, G. A., Chiu, F.-C., Brosnan, CF., Bornstein, M.B. and Raine, C.S. Antigen-specific T cells can mediate demyelination in organotypic central nervous system cultures. Cell.Immunol. 102: 217–226, 1986.PubMedCrossRefGoogle Scholar
  3. 3.
    Brosnan, C.S., Selmaj, K. and Raine, C.S. Hypothesis: A role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis. J. Neuroimmunol. 18: 87–94, 1988.PubMedCrossRefGoogle Scholar
  4. 4.
    Prineas, J.W. and Raine, C.S. Electron microscopy and immunoperoxidase studies of early multiple sclerosis lesions. Neurology 26: 29–32, 1976.PubMedCrossRefGoogle Scholar
  5. 5.
    Prineas, J.W. and Graham, J.S. Multiple sclerosis: Capping of surface immunoglobulin G on macrophages engaged in myelin break down. Ann.Neurol. 10: 149–158, 1981.PubMedCrossRefGoogle Scholar
  6. 6.
    Compston, D.A.S., Morgan, B.P., Oleesky, D., Fifield, R. and Campbell, A.K. Cerebrospinal fluid C9 in demyelinating disease. Neurology 36: 1503–1506, 1986.PubMedCrossRefGoogle Scholar
  7. 7.
    Scolding, N.J., Morgan, B.P., Houston, W.A.J., Linington, C., Campbell, A.K. and Compston, D.A.S. Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature 339: 620–622, 1989.PubMedCrossRefGoogle Scholar
  8. 8.
    Compston, D.A.S., Morgan, B.P., Campbell, A.K., Wilkins, P., Cole, G., Thomas, N.D. and Jasani, B. Immunocytochemical Localization of the Terminal Complement Complex in Multiple Sclerosis Neuropathol. Appl. Neurobiol. 15: 307–316, 1989.CrossRefGoogle Scholar
  9. 9.
    Esiri, M.M. Multiple sclerosis: a quantitative and qualitative study of Ig-containing cells in the CNS. Neuropathol. Appl. Neurobiol. 6: 9–21, 1980.PubMedCrossRefGoogle Scholar
  10. 10.
    Newcombe, J.I.A., Ganan, S. and Cuzner, M.L. Serum antibodies against central nervous system proteins in human demyelinating disease. Clin.Exp.Immunol. 59: 383–390, 1985.PubMedGoogle Scholar
  11. 11.
    Waksman, B.H., Porter, H., Lees, M.B., Adams, R.D. and Folch, J. A study of the chemical nature of components of bovine white matter effective in producing allergic encephalomyelitis in the rabbit. J. Exp.Med. 100: 451–471, 1954.PubMedCrossRefGoogle Scholar
  12. 12.
    Raine, C.S. Experimental allergic encephalomyelitis and experimental allergic neuritis. In: Handbook of Clinical Neurology, edited by Vinken, Bruyn, and Klawans, Elsevier Sc.Publ., 1985, p. 429–466.Google Scholar
  13. 13.
    Lassmann, H. Comparative neuropathology of chronic experimental allergic encephalomyelitis und multiple sclerosis, Berlin: Springer Verlag, 1983.CrossRefGoogle Scholar
  14. 14.
    Williams, R.M., Lees, M.B., Cambi, F. and Macklin, W.B. Chronic experimental allergic encephalomyelitis induced in rabbits with bovine white matter proteolipid apoprotein. J. Neuropathol.Exp.Neurol. 41: 508–521, 1982.PubMedCrossRefGoogle Scholar
  15. 15.
    Lassmann, H., Brunner, C., Bradi, M. and Linington, C. Experimental allergic encephalomyelitis: The balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol. 75: 566–576, 1988.PubMedCrossRefGoogle Scholar
  16. 16.
    Bornstein, M.B. and Raine, C.S. Multiple sclerosis and experimental allergic encephalomyelitis: Specific demyelination of CNS in culture. Neuropathol. Appl.Neurobiol. 3: 359–367, 1977.CrossRefGoogle Scholar
  17. 17.
    Brosnan, CF., Stoner, G.L., Bloom, B.R., Wisniewski, H.M. Studies on demyelination by activated lymphocytes in the rabbit eye II. Antibody-dependant cell-mediated demyelination. J. Immunol. 118: 2103–2110, 1977.PubMedGoogle Scholar
  18. 18.
    Lassmann, H., Stemberger, H., Kitz, K. and Wisniewski, H.M. In vivo demyelinating activity of sera from animals with chronic experimental allergic encephalomyelitis. Antibody nature of the demyelinating factor and the role of complement J. Neurol.Sci. 59: 123–137, 1983.Google Scholar
  19. 19.
    Raine, C.S., Johnson, A.B., Marcus, D.M., Suzuki, A. and Bornstein, M.B. Demyelination in vitro. Absorption studies demonstrate that galactocerebroside is a major target. J. Neurol.Sci. 52: 117–131, 1981.PubMedCrossRefGoogle Scholar
  20. 20.
    Lebar, R. and Voisin, G.A. Studies on auto-immune encephalomyelitis in the guinea pig. I. Influence of different immunizations on antibodies specificity and biological properties, relation to the incidence of the disease. Int.Arch.Allergy Appl.Immunol. 46: 82–103, 1974.PubMedCrossRefGoogle Scholar
  21. 21.
    Lebar, R., Lubetzki, C., Vincent, C., Lombrail, P. and Poutry, J.-M. The M2 autoantigen of central nervous system myelin, a glycoprotein present in oligodendrocyte membranes. Clin.Exp.Immunol. 66: 23–443, 1986.Google Scholar
  22. 22.
    Linington, C. and Lassmann, H. Antibody responses in chronic relapsing experimental allergic encephalomyelitis: Correlation of serum demyelinating activity with antibody titer to myelin/oligodendrocyte glycoprotein (MOG). J. Neuroimmunol. 17: 61–70, 1987.PubMedCrossRefGoogle Scholar
  23. 23.
    Linington, C., Webb, M. and Woodhams, P.L. A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody. J. Neuroimmunol. 6: 387–396, 1984.CrossRefGoogle Scholar
  24. 24.
    Sun, J., Link, H., Olsson, H., Xiao, B., Andersson, G., Ekre, H.-P., Linington, C. and Diener, P. T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J. Immunol. 146: 1490–1495.1991.Google Scholar
  25. 25.
    Xiao, B., Linington, C. and Link, H. Antibodies to myelin-oligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls. J. Neuroimmunol. 31: 91–96, 1991.PubMedCrossRefGoogle Scholar
  26. 26.
    Linington, C., Bradi, M., Lassmann, H., Brunner, C. and Vass, K. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am.J. Pathol. 130: 443–454, 1988.PubMedGoogle Scholar
  27. 27.
    Brunner, C., H. Lassmann, T.V. Waehneldt, J.-M. Matthieu and C. Linington: Differential ultrastructural localisation of myelin basic protein, myelin/oligodendrocyte glycoprotein and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase in the CNS of adult rats. J. Neurochem. 52, 296–304 (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    Amiguet, P., Gardinier, M.V., Zanetta, J.-P. and Matthieu, J.-M. Purification and partial structural and functional characterization of mouse myelin/oligodendrocyte glycoprotein. J. Neurochem. 58: 1676–1682.1992.Google Scholar
  29. 29.
    Gardinier, M.V., Amiguet, P., Linington, C. and Matthieu, J.-M. Myelin/oligodendrocyte glycoprotein is a unique member of the immunoglobulin superfamily. J. Neurosci.Res. 33: 177–187, 1992.PubMedCrossRefGoogle Scholar
  30. 30.
    Lassmann, H., Zimprich, F., Rossler, K. and Vass, K. Inflammation in the nervous system. Basic mechanisms and immunological concepts. Rev.Neurol. 147: 763–781, 1991.PubMedGoogle Scholar
  31. 31.
    Lassmann, H. and C. Linington: The role of antibodies against myelin surface antigens in chronic EAE. In: A multidisciplinary approach to Myelin diseases. Ed: G. S. Crescenzi. NATO ASI Series Vol A142, Plenum Press New York, pp 219–226, 1987.Google Scholar
  32. 32.
    Linington, C., B.P. Morgan, N.J. Scolding, S. Piddlesden, P. Wilkins and D.A.S. Compston. The role of complement in the pathogenesis of experimental allergic encephalomyelitis. Brain112: 895–911, 1PubMedCrossRefGoogle Scholar
  33. 33.
    Kerlero de Rosbo, N., Honegger, P., Lassmann, H. and Matthieu, J.-M. Demyelination induced in aggregating brain cell cultures by a monoclonal antibody against myelin/oligodendrocyte glycoprotein. J. Neurochem. 55: 583–587, 1990.PubMedCrossRefGoogle Scholar
  34. 34.
    Lebar, R. and Voisin, G.A. Studies on auto-immune encephalomyelitis in the guinea pig. I. Influence of different immunizations on antibodies specificity and biological properties, relation to the incidence of the disease. Int.Arch.Allergy Appl.Immunol. 46: 82–103, 1974.PubMedCrossRefGoogle Scholar
  35. 35.
    Schluesener, HJ., Sobel, R.A., Linington, C. and Weiner, H.L. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J. Immunol. 139: 4016–4021, 1987.PubMedGoogle Scholar
  36. 36.
    Linington, C., Lassmann, H., Morgan, B.P. and Compston, D.A.S. Immunohistochemical localization of terminal complement component C′9 in experimental allergic encephalomyelitis. Acta Neuropathol. 79: 78–85, 1989.PubMedCrossRefGoogle Scholar
  37. 37.
    Piddlesden, S., Lassmann, H., Laffafian, I., Morgan, B.P. and Linington, C. Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation. Clin.Exp.Immunol. 83: 245–250, 1991.PubMedCrossRefGoogle Scholar
  38. 39.
    Wekerle, H. Myelin specific, autoaggressive T cell clones in the normal immune repertoire: their nature and their regulation. Intern. Rev. Immunol. 9: 231–241, 1992.CrossRefGoogle Scholar
  39. 40.
    Dyrberg, T. Molecular mimicry in autoimmunity, in: Molecular Autoimmunity, Academic Press, New York (1991).Google Scholar
  40. 41.
    Jahnke, U., Fischer, E.H. and Alvord, E.C. Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis. Science 229: 282–284, 1985.PubMedCrossRefGoogle Scholar
  41. 42.
    Fujinami, R.S. and Oldstone, M.B.A. Amino acid homology between the encephalitogenic site of myelin basic protein (MBP) and virus: Mechanism for autoimmunity. Science 230: 1043–1046, 1985.PubMedCrossRefGoogle Scholar
  42. 43.
    Jack, L.J.W. and Mather, I.H. Cloning and analysis of cDNA encoding bovine butyrophilin, an apical glycoprotein expressed in mammary tissue and secreted in association with the milk-fat globule membrane during lactation. J. Biol. Chem. 265: 14481–14486, 1990.PubMedGoogle Scholar
  43. 44.
    Karjalainen, J., Martin, J.M., Knip, M., Ilonen, J. et al. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. New. Eng. J. Med. 327: 302–307, 1992.PubMedCrossRefGoogle Scholar
  44. 45.
    Longenecker, B.M. and Mossman, T.R. “Natural”antibodies to chicken MHC antigens are present in mice, rats, humans, alligators, and allogeneic chickens. Immunogenetics 11: 293–302.Google Scholar
  45. 46.
    Blumberg, B.M., Crowley, J.C., Silverman, J.I., Menonna, J., Cook, S.D. and Dowling, P.C. Measles virus L protein evidences elements of ancestral RNA polymerase. Virology 164: 487–497, 1988.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Christopher Linington
    • 1
  • Martin Adelmann
    • 1
  • Roxana Popovici
    • 1
  1. 1.Max-Planck-Institut fr PsychiatriePlanegg-MartinsriedGermany

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