Journal of Neurology

, Volume 252, Supplement 5, pp v3–v9 | Cite as

The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage

  • Wolfgang Brück


Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system manifested morphologically by inflammation, demyelination, axonal loss and gliosis. The inflammatory lesions are characterized by massive infiltration by a heterogeneous population of cellular and soluble mediators of the immune system, including T cells, B cells, macrophages and mi croglia, as well as a broad range of cytokines, chemokines, antibodies, complement and other toxic substances. The appearance of such lesions is associated with clinical relapses. Recent detailed immunopathological studies of early, acute lesions revealed profound heterogeneity in the patterns of demyelination and the factors of the immune system involved. During remission, resolution of inflammation is the main factor which leads to clinical improvement of patients. However, the immune system can play a beneficial role at this stage, promoting remyelination perhaps by production of growth factors such as BDNF. In contrast, the progressive irreversible neurological deficit in multiple sclerosis is associated with neurodegenerative processes resulting in axonal and neuronal loss. The mechanisms behind damage to axons in multiple sclerosis lesions are poorly understood. However, the close proximity of areas with prominent axonal loss and areas containing inflammatory infiltrates (e. g., T cells, macrophages) suggest that axonal damage is closely associated with inflammation. Different soluble or cellular mediators of the immune response have been shown to damage axons in experimental systems, and these may be responsible for neurodegeneration in human disease.

Key words

multiple sclerosis neurodegeneration inflammation pathophysiology histopathology 


  1. 1.
    Aktas O, Smorodchenko A, Brocke S, Infante-Duarte C, Topphoff US, Vogt J, Prozorovski T, Meier S, Osmanova V, Pohl E, Bechmann I, Nitsch R, Zipp F (2005) Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46:421–432CrossRefPubMedGoogle Scholar
  2. 2.
    Barkhof F, Bruck W, De Groot CJ, Bergers E, Hulshof S,Geurts J, Polman CH, van der Valk P (2003) Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch Neurol 60:1073–1081CrossRefPubMedGoogle Scholar
  3. 3.
    Besser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophin brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2 polarised expression of their receptors. J Immunol 162:6303–6306PubMedGoogle Scholar
  4. 4.
    Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123:1174–1183CrossRefPubMedGoogle Scholar
  5. 5.
    D’Souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, Raine CS, Antel JP (1996) Multiple sclerosis: Fas signaling in oligodendrocyte cell death. J Exp Med 184:2361–2370CrossRefPubMedGoogle Scholar
  6. 6.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399CrossRefPubMedGoogle Scholar
  7. 7.
    Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870CrossRefPubMedGoogle Scholar
  8. 8.
    Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R (2003) Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 53:292–304CrossRefPubMedGoogle Scholar
  9. 9.
    Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276PubMedGoogle Scholar
  10. 10.
    Kuhlmann T, Lingfield G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212CrossRefPubMedGoogle Scholar
  11. 11.
    Lovas G, Szilagyi N, Majtenyi K, Palkovits M, Komoly S (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123:308–317CrossRefPubMedGoogle Scholar
  12. 12.
    Lucchinetti, C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717CrossRefPubMedGoogle Scholar
  13. 13.
    Matysiak M, Jurewicz A, Jaskolski D, Selmaj K (2002) TRAIL induces death of human oligodendrocytes isolated from adult brain. Brain 125:2469–2480CrossRefPubMedGoogle Scholar
  14. 14.
    Mead RJ, Singhrao SK, Neal JW, Lassmann H, Morgan BP (2002) The membrane attack complex of complement causes severe demyelination associated with acute axonal injury. J Immunol 68:458–465Google Scholar
  15. 15.
    Medana IM, Gallimore A,Oxenius A, Martinic MM, Wekerle H, Neumann H (2000) MHC class I-restricted killing of neurons by virus-specific CD8 + T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol 30:3623–3633CrossRefPubMedGoogle Scholar
  16. 16.
    Mews I, Bergmann M, Bunkowski S, Gullotta F, Bruck W (1998) Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler 4:55–62CrossRefPubMedGoogle Scholar
  17. 17.
    Murray PD, McGavern DB, Lin X, Njenga MK, Leibowitz J, Pease LR, Rodriguez M (1998) Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J Neurosci 18:7306–7314PubMedGoogle Scholar
  18. 18.
    Neumann H, Medana IM, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25:313–319CrossRefPubMedGoogle Scholar
  19. 19.
    Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H (1997) Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med 185:305–316CrossRefPubMedGoogle Scholar
  20. 20.
    Okuda Y, Bernard CC, Fujimura H, Yanagihara T, Sakoda S (1998) Fas has a crucial role in the progression of experimental autoimmune encephalomyelitis. Mol Immunol 35:317–326CrossRefPubMedGoogle Scholar
  21. 21.
    Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400CrossRefPubMedGoogle Scholar
  22. 22.
    Pitt D, Werner P, Raine CS (2000) Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6:67–70CrossRefPubMedGoogle Scholar
  23. 23.
    Pouly S, Antel JP (1999) Multiple sclerosis and central nervous system demyelination. J Autoimmun 13:297–306CrossRefPubMedGoogle Scholar
  24. 24.
    Redford EJ, Kapoor R, Smith KJ (1997) Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120:2149–2157CrossRefPubMedGoogle Scholar
  25. 25.
    Rubesa G, Podack ER, Sepcic J, Rukavina D (1997) Increased perforin expression in multiple sclerosis patients during exacerbation of disease in peripheral blood lymphocytes. J Neuroimmunol 74:198–204CrossRefPubMedGoogle Scholar
  26. 26.
    Smith KJ, Kapoor R, Hall SM, Davies M (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470–476CrossRefPubMedGoogle Scholar
  27. 27.
    Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85CrossRefPubMedGoogle Scholar
  28. 28.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  29. 29.
    Vergelli M, Hemmer B, Muraro PA, Tranquill L, Biddison WE, Sarin A, Mc-Farland HF, Martin R (1997) Human autoreactive CD4 + T cell clones use perforin- or Fas/Fas ligand-mediated pathways for target cell lysis. J Immunol 158:2756–2761PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  1. 1.Dept. of NeuropathologyUniversity Hospital Georg-August-UniversityGöttingenGermany

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