, Volume 41, Issue 5, pp 365–373 | Cite as

Mechanisms Underlying the Process of Demyelination in Multiple Sclerosis



The author generalizes and analyzes the published data and her own findings related to the cellular and molecular mechanisms underlying a demyelinating disease, multiple sclerosis. The mechanisms of the immunopathogenic process in multiple sclerosis, the involvement of microglia and astrocytes in destruction of the myelin sheaths, and injury of oligodendrocytes are discussed. Experimental models used for examination of the processes of demyelination of the nerve tissue in vitro (tissue cultures) and in vivo (experimental allergic encephalomyelitis) are also described.


multiple sclerosis demyelination glia in vitro and in vivo models of demyelination. 


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  1. 1.
    T. J. Murray, “The history of multiple sclerosis,” in: Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation, Demos Medical, New York (2000).Google Scholar
  2. 2.
    J. Zajicek, “The epidemiology of multiple sclerosis,” J. Neurol., 254, No. 12, 1742 (2007).CrossRefPubMedGoogle Scholar
  3. 3.
    S. M. Vinnichouk and O. A. Myalovitskaya, Multiple Sclerosis [in Russian], Kompolis, Kyiv (2001).Google Scholar
  4. 4.
    A. Bar-Or, E. M. L. Oliveira, D. E. Anderson, et al., “Molecular pathogenesis of multiple sclerosis,” J. Neuroimmunol., 100, Nos. 1/2, 252-259 (1999).CrossRefPubMedGoogle Scholar
  5. 5.
    Y. Galboiz and A. Miller, “Immunological indicators of disease activity and prognosis in multiple sclerosis,” Curr. Opin. Neurol., 15, No. 3, 233-237 (2002).CrossRefPubMedGoogle Scholar
  6. 6.
    J. Antel and D. Arnold, “Multiple sclerosis,” in: Neuroglia, Oxford Univ. Publ., New York (2005).Google Scholar
  7. 7.
    S. Sawcer, P. N. Goodfellow, and A. Compston, “The genetic analysis of multiple sclerosis,” Trends Gen., 13, No. 6, 234-239 (1997).CrossRefGoogle Scholar
  8. 8.
    C. C. C. Bernard and N. K. de Rosbo, “Multiple sclerosis: an autoimmune disease of multifactorial etiology,” Curr. Opin. Immunol., 4, No. 6, 760-765 (1992).CrossRefPubMedGoogle Scholar
  9. 9.
    A. P. Khokhlov and Yu. N. Savchenko, “Myelin and molecular bases of the process of demyelination,” Korsakov Zh. Nevropatol. Psykhiat., 90, No. 8, 104-109 (1990).Google Scholar
  10. 10.
    B. Kornek, M. K. Storch, R. Weissert, et al., “Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions,” Am. J. Pathol., 157, No. 1, 267-276 (2000).PubMedGoogle Scholar
  11. 11.
    B. C Kieseier, M. K. Storch, J. J. Archelos, et al., “Effector pathways in immune mediated central nervous system ddemyelination,” Curr. Opin. Neurol., 12, No. 3, 323-336 (1999).CrossRefPubMedGoogle Scholar
  12. 12.
    B.-G. Xiao and H. Link, “Antigen-specific T cells in autoimmune diseases with a focus on multiple sclerosis and experimental allergic encephalomyelitis,” Cell. Mol. Life Sci., 56, Nos. 1/2, 5-21 (1999).CrossRefPubMedGoogle Scholar
  13. 13.
    B. C. Kieseier, T. Seifert, G. Giovannoni, et al., “Matrix metalloproteinases in inflammatory ddemyelination: targets for treatment,” Neurology, 53, No. 1, 20-25 (1999).PubMedGoogle Scholar
  14. 14.
    B. P. Morgan, P. Gasque, S. Singhrao, et al., “The role of complement in disorders of the nervous system,” Immunopharmacology, 38, Nos. 1/2, 43-50 (1997).CrossRefPubMedGoogle Scholar
  15. 15.
    E. N. Benveniste, “Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis,” J. Mol. Med., 75, No. 3, 165-173 (1997).CrossRefPubMedGoogle Scholar
  16. 16.
    A. Chan, W. W. Tourtellotte, R. Rudick, et al., “Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system,” Glia, 33, No. 1, 87-95 (2001).CrossRefPubMedGoogle Scholar
  17. 17.
    Y. Dong and E. N. Benveniste, “Immune function of astrocytes,” Glia, 36, No. 2, 180-190 (2001).CrossRefPubMedGoogle Scholar
  18. 18.
    I. A. Zavalishnin, M. N. Zakharova, L. Sh. Askarova, et al., “Modern directions in investigation of pathogenesis of demyelinating diseases,” Korsakov Zh. Nevropatol. Psikhiat., 97, No. 5, 64-67 (1997).Google Scholar
  19. 19.
    M. E. Hatten, R. K. H. Liem, M. L. Shelanski, et al., “Astroglia in CNS injury,” Glia, 4, No. 2, 233-243 (1991).CrossRefPubMedGoogle Scholar
  20. 20.
    U. Slobodov, F. Reichert, R. Mirski, et al., “Distinct inflammatory stimuli induce different patterns of myelin phagocytosis and degradation in recruited macrophages,” Exp. Neurol., 167, No. 2, 401-409 (2001).CrossRefPubMedGoogle Scholar
  21. 21.
    M. E. Smith, “Phagocytosis of myelin in demyelinative disease: a review,” Neurochem. Res., 24, No. 2, 261-268 (1999).CrossRefPubMedGoogle Scholar
  22. 22.
    T. A. Springer, “Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm,” Cell, 76, No. 2, 301-314 (1994).CrossRefPubMedGoogle Scholar
  23. 23.
    B. Cannella and C. S. Raine, “The adhesion molecule and cytokine profile of multiple sclerosis lesions,” Ann. Neurol., 37, No. 4, 424-435 (1995).CrossRefPubMedGoogle Scholar
  24. 24.
    S. J. Lee and E. N. Benveniste, “Adhesion molecule expression and regulation on cells of the central nervous system,” J. Neuroimmunol., 98, No. 2, 77-88 (1999).CrossRefPubMedGoogle Scholar
  25. 25.
    A. Svenningsson, G. K. Hansson, O. Andersen, et al., “Adhesion molecule expression on cerebrospinal fluid T lymphocytes: evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls,” Ann. Neurol., 34, No. 2, 155-161 (1993).CrossRefPubMedGoogle Scholar
  26. 26.
    R. A. Sobel, M. E. Mitchell, and G. Fondren, “Intercellular adhesion molecule-1 (ICAM-1) in cellular immune reactions in the human central nervous system,” Am. J. Pathol., 136, No. 6, 1309-1316 (1990).PubMedGoogle Scholar
  27. 27.
    C. F. Brosnan, B. Cannella, L. Batistini, et al, “Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and reactive nitrogen species,” Neurology, 45, Suppl. 6, S16-S21 (1995).PubMedGoogle Scholar
  28. 28.
    J. J. Archelos and H. P. Hartung, “The role of adhesion molecules in multiple sclerosis: biology, pathogenesis and therapeutic implications,” Mol. Med. Today, 3, No. 7, 310-321(1997).CrossRefPubMedGoogle Scholar
  29. 29.
    N. K. Damle, K. Klussman, G. Leytze, et al., “Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7,” J. Immunol., 152, No. 6, 2686-2697 (1994).PubMedGoogle Scholar
  30. 30.
    H. P. Hartung, J. J. Archelos, J. Zielasek, et al., “Circulating adhesion molecules and inflammatory mediators in demyelination: a review,” Neurology, 45, Suppl. 6, S22-S32 (1995).PubMedGoogle Scholar
  31. 31.
    H. P. Hartung, K. Reiners, J .J. Archelos, et al., “Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging,” Ann. Neurol., 38, No. 2, 186-193 (1995).CrossRefPubMedGoogle Scholar
  32. 32.
    B. T. Fife, G. B. Huffnagel, W. A. Kuziel, et al., “Chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis,” J. Exp. Med., 192, No. 6, 899-905 (2000).CrossRefPubMedGoogle Scholar
  33. 33.
    R. Gold, H.-P. Hartung, K. V. Toyka, “Animal models for autoimmune demyelinating disorders of the nervous system,” Mol. Med. Today, 6, No. 2, 88-91 (2000).CrossRefPubMedGoogle Scholar
  34. 34.
    T. L. Sorensen, M. Tani, J. Jensen, et al., “Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients,” J. Clin. Invest., 103, No. 6, 807-815 (1999).CrossRefPubMedGoogle Scholar
  35. 35.
    J. Hvas. C. McLean, J. Justesen, et al., “Perivascular T cells express the pro-inflammatory chemokine RANTES mRNA in multiple sclerosis lesions,” Scand. J. Immunol., 46, No. 2, 195-203 (1997).CrossRefPubMedGoogle Scholar
  36. 36.
    C. McManus, J. W. Berman, F. M. Brett, et al., “MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study,” J. Neuroimmunol., 86, No. 1, 20-29 (1998).CrossRefPubMedGoogle Scholar
  37. 37.
    P. Van Der Voorn, J. Tekstra, R. H. Beelen, et al., “Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions,” Am. J. Pathol., 154, No. 1, 45-51 (1999).Google Scholar
  38. 38.
    A. D. Luster, “Chemokines – chemotactic cytokines that mediate inflammation,” New Engl. J. Med., 338, No. 7, 436-445 (1998).CrossRefPubMedGoogle Scholar
  39. 39.
    S. G. Ward, K. Bacon, and J. Westwick, “Chemokines and T lymphocytes: more than an attraction,” Immunity, 9, No. 1, 1-11 (1998).CrossRefPubMedGoogle Scholar
  40. 40.
    L. Izikson, R. S. Klein, I. F. Charo, et al., ”Resistance to experimental autoimmune encephalomyelitis in mice lacking the CCchemokine receptor (CCR)2,” J. Exp. Med., 192, No. 7, 1075-1080 (2000). CrossRefPubMedGoogle Scholar
  41. 41.
    D. C. Anthony, K. M. Miller, S. Fearn, et al., “Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS,” J. Neuroimmunol., 87, Nos. 1/2, 62-72 (1998).CrossRefPubMedGoogle Scholar
  42. 42.
    R. A. Black, C. T. Rauch, C. J. Kozlosky, et al., “A metalloproteinase disintegrin that releases tumor-necrosis factor-alpha from cells,” Nature, 385, No. 6618, 729-733 (1997).CrossRefPubMedGoogle Scholar
  43. 43.
    E. Ambrosini and F. Aloisi, “Chemokines and glial cells: a complex network in the central nervous system,” Neurochem. Res., 29, No. 5, 1017-1038 (2004).CrossRefPubMedGoogle Scholar
  44. 44.
    J. E. Merrill and E. N. Benveniste, “Cytokines in inflammatory brain lesions: helpful and harmful,” Trends Neurosci., 19, No. 8, 331-338 (1996).CrossRefPubMedGoogle Scholar
  45. 45.
    R Brett and M. G. Rumsby, “Evidence of free radical damage in the central nervous system of guinea-pigs at the prolonged acute and early relapse stages of chronic relapsing experimental allergic encephalomyelitis,” Neurochem. Int., 23, No. 1, 35-44 (1993).CrossRefPubMedGoogle Scholar
  46. 46.
    B Mitrovic, L. J. Ignarro, H. V. Vinters, et al., “Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes,” Neuroscience, 65, No. 2, 531-539 (1995).CrossRefPubMedGoogle Scholar
  47. 47.
    T. A. Pivneva, E. V. Kolotushkina, and N. A. Mel’nik, “Mechanisms of the demyelination process and its modeling,” Neurophysiology, 31, No. 6, 403-412 (1999).CrossRefGoogle Scholar
  48. 48.
    G. A. Roth, V. Spada, K. Hamill, et al., “Insulin-like growth factor I increases myelination and inhibits demyelination in cultured organotypic nerve tissue,” Brain Res. Dev. Brain Res., 88, No. 1, 102-108 (1995).CrossRefPubMedGoogle Scholar
  49. 49.
    G. G. Skibo and L. M. Koval’, Structural Regularities of the Development of Neurons under Conditions of Culturing [in Russian], Naukova Dumka, Kyiv (1992).Google Scholar
  50. 50.
    N. J. Abbott, “Astrocyte-endothelial interactions and blood-brain barrier permeability,” J. Anat., 200, No. 6, 629-638 (2002).CrossRefPubMedGoogle Scholar
  51. 51.
    V. P. Bozhkova, P. D. Brezhestovskii, V. P. Byravlev, et al., Manual of Culturing of Nerve Tissue: Methods, Technical Equipment, Problems [in Russian], Nauka, Moscow (1988).Google Scholar
  52. 52.
    L. M. Notterpek and L. H. Rome, “Functional evidence for the role of axolemma in CNS myelination,” Neuron, 13, No. 2, 473-485 (1994).CrossRefPubMedGoogle Scholar
  53. 53.
    B. D. Trapp, H. D. Webster, D. Johnson, et al., “Myelin formation in rotation-mediated aggregating cell cultures: immunocytochemical, electron microscopic, and biochemical observations,” J. Neurosci., 2, No. 7, 986-993 (1982).PubMedGoogle Scholar
  54. 54.
    L. Hertz, L. Peng, and J. C. Lai, “Functional studies in cultured astrocytes,” Methods, 16, No. 3, 293-310 (1998).CrossRefPubMedGoogle Scholar
  55. 55.
    R. C. Melcangi, M. Ballabio, M. Magnaghi, et al., “Metabolism of steroids in pure cultures of neurons and glial cells: role of intracellular signalling,” J. Steroid Biochem. Mol. Biol., 53, Nos. 1/6, 331-336 (1995).CrossRefPubMedGoogle Scholar
  56. 56.
    D. D. Murphy and S. B. Andrews, “Culture models for the study of estradiol-induced synaptic plasticity,” J. Neurocytol., 29, Nos. 5/6, 411-417 (2000).CrossRefPubMedGoogle Scholar
  57. 57.
    S. Raval-Fernandez and L. H. Rome, “Role of axonal components during myelination,” Microsc. Res. Tech., 41, No. 5, 379-392 (1998).CrossRefGoogle Scholar
  58. 58.
    N. Ben-Ari, V. Tseeb, D. Raggozzino, et al., “Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life,” Prog. Brain Res., 102, 261-273 (1994).CrossRefPubMedGoogle Scholar
  59. 59.
    E. Zapryanova, O. S. Sotnikov, S. S. Sergeeva, et al., “Axon reactions precede demyelination in experimental models of multiple sclerosis,” Neurosci. Behav. Physiol., 34, No. 4, 337-342 (2004).CrossRefPubMedGoogle Scholar
  60. 60.
    A. M. Baker, M. C. Grekova, and J. R. Richert, “EAE susceptibility in FVB mice,” J. Neurosci. Res., 61, No. 2, 140-145 (2000).CrossRefPubMedGoogle Scholar
  61. 61.
    A. Ben-Nun, I. Mendel, and N. Kerlero de Rosbo, “Immunomodulation of murine experimental autoimmune encephalomyelitis by pertussis toxin: the protective activity, but not the disease-enhancing activity, can be attributed to the nontoxic B-oligomer,” Proc. Assoc. Am. Physicians, 109, No. 2, 120-125 (1997).PubMedGoogle Scholar
  62. 62.
    I. Mendel, N. Kerlero de Rosbo, and A. Ben-Nun, “The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease,” J. Neurol., 243, Suppl. 1, S14-S22 (1996).PubMedGoogle Scholar
  63. 63.
    Yu. M. Zhabotinskii and V. I. Ioffe, Experimental Allergic Demyelinating Diseases of the Nervous System [in Russian], Meditsina, Leningrad (1975).Google Scholar
  64. 64.
    E. Gunther, H. Odenthal, and W. Wechsler, “Association between susceptibility to experimental allergic encephalomyelitis and the major histocompatibility system in congenic rat strains,” Clin. Exp. Immunol., 32, No. 3, 429-434 (1978).PubMedGoogle Scholar
  65. 65.
    M. K. Storch, A. Sterferl, U. Brehm, et al., “Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology,” Brain Pathol., 8, No. 4, 681-694 (1998).PubMedCrossRefGoogle Scholar
  66. 66.
    R. Gold, H.-P. Hartung, and H. Lassmann, “T-cell apoptosis in autoimmune diseases: termination of inflammation in the nervous system and other sites with specialized immune-defense mechanisms,” Trends Neurosci., 20, No. 9, 399-404 (1997).CrossRefPubMedGoogle Scholar
  67. 67.
    P. Hjelmstrom, A. E. Juedes, J. Fjell, et al., “B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization,” J. Immunol., 161, No. 9, 4480-4483 (1998).PubMedGoogle Scholar
  68. 68.
    H. Lassmann, “Models of multiple sclerosis: new insights into pathophysiology and repair,” Curr. Opin. Neurol., 21, No. 3, 242-247 (2008).CrossRefPubMedGoogle Scholar
  69. 69.
    G. L. Boccaccio and L. Steinman, “Multiple sclerosis: from a myelin point of view,” J. Neurosci. Res., 45, No. 6, 647-654 (1996).CrossRefPubMedGoogle Scholar
  70. 70.
    B. Kalman and F. D. Lublin, “Cytokine therapy,” in: Immunotherapy in Neuroimmunologic Diseases, Martin Dunitz, London (1998).Google Scholar
  71. 71.
    R. M. Ransohoff, “Chemokines in neurological disease models: correlation between chemokine expression patterns and inflammatory pathology,” J. Leukoc. Biol., 62, No. 5, 645-652 (1997).PubMedGoogle Scholar
  72. 72.
    M. Ding, M. Zhang, J. L. Wong, et al., “Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice,” J. Immunol., 160, No. 6, 2560-2564 (1998).PubMedGoogle Scholar
  73. 73.
    M. P. Pender, “Demyelination and neurological signs in experimental allergic encephalomyelitis,” J. Neuroimmunol., 15, No. 1, 11-24 (1987).CrossRefPubMedGoogle Scholar
  74. 74.
    K. W. Selmaj and C. S. Raine, “Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro,” Ann. Neurol., 23, No. 4, 339-346 (1988).CrossRefPubMedGoogle Scholar
  75. 75.
    J. Bauer, I. Huitinga, W. Zhao, et al., “The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis,” Glia, 15, No. 4, 437-446 (1995).CrossRefPubMedGoogle Scholar
  76. 76.
    M. Mayer-Proschel, M. S. Rao, and M. Noble, “Progenitor cells of the central nerve system: a boon for clinical neuroscience,” J. NIH Res., 9, 31-36 (1997).Google Scholar
  77. 77.
    J. A. Kawszak, M. M. Mathisen, J. A. Drazba, et al., “Digitized image analysis reveals diffuse abnormalities in normal-appearing white matter during acute experimental autoimmune encephalomyelitis,” J. Neurosci. Res., 54, No. 3, 364-372 (1998).CrossRefGoogle Scholar
  78. 78.
    Y. Matsumoto, K. Ohmori, and M. Fujiwara, “Microglial and astroglial reactions to inflammatory lesions of experimental autoimmune encephalomyelitis in the rat central nervous system,” J. Neuroimmunol., 37, Nos. 1/2, 23-33 (1992).CrossRefPubMedGoogle Scholar
  79. 79.
    X. Liu, D-L. Yao, C. A. Bondy, et al., “Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis,” Mult. Scler., 1, No. 1, 2-9 (1995).PubMedGoogle Scholar
  80. 80.
    C Fressinaud and J. M. Vallat, “Basic fibroblast growth factor improves recovery after chemically induced breakdown of myelin-like membranes in pure oligodendrocyte cultures,” J. Neurosci. Res., 38, No. 2, 202-213(1994).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2009

Authors and Affiliations

  1. 1.Bogomolets Institute of PhysiologyNational Academy of Sciences of UkraineKyivUkraine

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