Advertisement

Clinical Reviews in Allergy & Immunology

, Volume 42, Issue 1, pp 26–34 | Cite as

Current Concepts in Multiple Sclerosis: Autoimmunity Versus Oligodendrogliopathy

  • Jin Nakahara
  • Michiko Maeda
  • Sadakazu Aiso
  • Norihiro Suzuki
Article

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects millions of patients worldwide. The current disease-modifying therapies (DMTs) that are widely used to treat MS only show modest effects. Because MS is a chronic disease, it is important to develop treatments that have better long-term efficacy. Recently, several new-generation DMTs have been developed, most of which target specific immune molecules based on the assumption that MS is an autoimmune disease. These DMTs are designed to inhibit inflammation that is thought to directly cause demyelination. Preliminary studies suggest that these new therapies are likely to show a greater effect in reducing relapses in early MS patients, although their long-term efficacy is still unknown. In contrast, it was recently reported that the initial course of MS does not significantly influence long-term disability and that disability increases approximately at the same rate despite variable relapse frequencies. Furthermore, new neuropathological evidence now argues against the autoimmune hypothesis and suggests that MS is a primary oligodendrogliopathy disease in which the inflammatory response may be a mere epiphenomenon. So can we be optimistic about the unproven long-term outcomes of new DMTs or should we reconsider the pathogenesis of MS when developing more disease-specific treatments?

Keywords

Multiple sclerosis Pathogenesis Autoimmune Oligodendrogliopathy 

Notes

Acknowledgments

Jin Nakahara is supported by the Keio University KANRINMARU Project. This work was supported by research grant #09-24 from the National Institute of Biomedical Innovation of Japan, by Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and by Grants-in-Aid for Scientific Research from MEXT.

References

  1. 1.
    The IFNβ Multiple Sclerosis Study Group (1993) Interferon β-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661Google Scholar
  2. 2.
    The Multiple Sclerosis Collaborative Research Group (1996) Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285–294CrossRefGoogle Scholar
  3. 3.
    The Copolymer 1 Multiple Sclerosis Study Group (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 45:1268–1276Google Scholar
  4. 4.
    Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain 129:606–616PubMedCrossRefGoogle Scholar
  5. 5.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468PubMedCrossRefGoogle Scholar
  6. 6.
    Henderson APD, Barnett MH, Parratt JDE et al (2009) Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 66:739–753PubMedCrossRefGoogle Scholar
  7. 7.
    Furtado GC, Marcondes MC, Latkowski JA et al (2008) Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J Immunol 181:4648–4655PubMedGoogle Scholar
  8. 8.
    Cua DJ, Sherlock J, Chen Y et al (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748PubMedCrossRefGoogle Scholar
  9. 9.
    Tzartos JS, Friese MA, Craner MJ et al (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells associated with active disease in multiple sclerosis. Am J Pathol 172:146–155PubMedCrossRefGoogle Scholar
  10. 10.
    Reboldi A, Coisne C, Baumjohann D et al (2009) C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523PubMedCrossRefGoogle Scholar
  11. 11.
    Esplugues E, Huber S, Gagliani N et al (2011) Controls of Th17 cells occurs in the small intestine. Nature 475:514–518PubMedCrossRefGoogle Scholar
  12. 12.
    Brown DA, Sawchenko PE (2007) Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J Comp Neurol 502:236–260PubMedCrossRefGoogle Scholar
  13. 13.
    Bartholomäus I, Kawakami N, Odoardi F et al (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:94–98PubMedCrossRefGoogle Scholar
  14. 14.
    Pang Y, Campbell L, Zheng B et al (2010) Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development. Neuroscience 166:464–475PubMedCrossRefGoogle Scholar
  15. 15.
    Lieberman AP, Pitha PM, Shin HS et al (1989) Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci USA 86:6348–6352PubMedCrossRefGoogle Scholar
  16. 16.
    Eugster HP, Frei K, Bachmann R et al (1999) Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur J Immunol 29:626–632PubMedCrossRefGoogle Scholar
  17. 17.
    Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JPY (2001) TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122PubMedCrossRefGoogle Scholar
  18. 18.
    Sriram S, Steiner I (2005) Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58:939–945PubMedCrossRefGoogle Scholar
  19. 19.
    Rivers TM, Sprunt DH, Berry GP (1933) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58:39–53PubMedCrossRefGoogle Scholar
  20. 20.
    Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60:12–21PubMedCrossRefGoogle Scholar
  21. 21.
    Waldor MK, Sriram S, Hardy R et al (1985) Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker. Science 227:415–417PubMedCrossRefGoogle Scholar
  22. 22.
    van Oosten BW, Lai M, Hodgkinson S et al (1997) Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 49:351–357PubMedGoogle Scholar
  23. 23.
    Ruddle NH, Bergman CM, McGrath KM et al (1990) An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172:1193–1200PubMedCrossRefGoogle Scholar
  24. 24.
    Selmaj K, Raine CS, Cross AH (1991) Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol 30:694–700PubMedCrossRefGoogle Scholar
  25. 25.
    The Lenercept Multiple Sclerosis Study Group, The University of British Columbia MS/MRI Analysis Group (1999) TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53:457–465Google Scholar
  26. 26.
    Sicotte NL, Voskuhl RR (2001) Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57:1885–1888PubMedGoogle Scholar
  27. 27.
    Robinson WH, Genovese MC, Moreland LW (2001) Demyelinating and neurologic events reported in association with tumor necrosis factor a antagonism: by what mechanisms could tumor necrosis factor a antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 44:1977–1983PubMedCrossRefGoogle Scholar
  28. 28.
    Segal BM, Constantinescu CS, Raychaudhuri A et al (2008) Repeated subcutaneous injections of IL12/23 p40 neutralizing antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomized, dose-ranging study. Lancet Neurol 7:796–804PubMedCrossRefGoogle Scholar
  29. 29.
    Lucchinetti C, Brück W, Parisi J et al (2000) Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 47:707–717PubMedCrossRefGoogle Scholar
  30. 30.
    Henderson AP, Barnett MH, Parratt JD, Prineas JW (2009) Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 66:739–753PubMedCrossRefGoogle Scholar
  31. 31.
    Kotter MR, Li WW, Zhao C et al (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332PubMedCrossRefGoogle Scholar
  32. 32.
    Rodriguez M, Warrington AE, Pease LR (2009) Human natural autoantibodies in the treatment of neurologic disease. Neurology 72:1269–1276PubMedCrossRefGoogle Scholar
  33. 33.
    Nielsen HH, Toft-Hansen H, Lambertsen KL, Owens T, Finsen B (2011) Stimulation of adult oligodendrogenesis by myelin-specific T cells. Am J Pathol, doi: 10.1016/j.ajpath.2011.06.006
  34. 34.
    Bradl M, Lassmann H (2010) Oligodendrocytes: biology and pathology. Acta Neuropathol 119:37–53PubMedCrossRefGoogle Scholar
  35. 35.
    Nakahara J, Kanekura K, Nawa M et al (2009) Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis. J Clin Invest 119:169–181PubMedGoogle Scholar
  36. 36.
    Charcot J (1868) Histologie de la sclérose en plaque. Gazette des Hôpitaux 41:554–566Google Scholar
  37. 37.
    Schumacher GA, Beebe G, Kibler RF et al (1965) Problems of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 122:552–568CrossRefGoogle Scholar
  38. 38.
    Poser CM, Paty DW, Scheinberg L et al (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231PubMedCrossRefGoogle Scholar
  39. 39.
    McDonald WI, Compston A, Edan G et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127PubMedCrossRefGoogle Scholar
  40. 40.
    Polman CH, Reingold SC, Banwell B et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302PubMedCrossRefGoogle Scholar
  41. 41.
    Vukusic S, Confavreux C (2003) Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci 206:135–137PubMedCrossRefGoogle Scholar
  42. 42.
    Confavreux C, Vukusic S (2006) Age at disability milestones in multiple sclerosis. Brain 129:595–605PubMedCrossRefGoogle Scholar
  43. 43.
    Hurwitz BJ (2011) Analysis of current multiple sclerosis registries. Neurology 76:S7–S13PubMedCrossRefGoogle Scholar
  44. 44.
    Brønnum-Hansen H, Koch-Henriksen N, Stenager E (2004) Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain 127:844–850PubMedCrossRefGoogle Scholar
  45. 45.
    Filippi M, Paty DW, Kappos L et al (1995) Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. Neurology 45:255–260PubMedGoogle Scholar
  46. 46.
    Losseff NA, Webb SL, O’Riordan JI et al (1996) Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 119:2009–2019PubMedCrossRefGoogle Scholar
  47. 47.
    Fisniku LK, Chard DT, Jackson JS et al (2008) Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64:247–254PubMedCrossRefGoogle Scholar
  48. 48.
    Fisher E, Lee JC, Nakamura K, Rudick RA (2008) Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 64:255–265PubMedCrossRefGoogle Scholar
  49. 49.
    Bonati U, Fisniku LK, Altmann DR et al (2011) Cervical cord and brain grey matter atrophy independently associate with long term MS disability. J Neurol Neurosurg Psychiatry 82:471–472PubMedCrossRefGoogle Scholar
  50. 50.
    Calabrese M, Rocca MA, Atzori M et al (2010) A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 67:376–383PubMedGoogle Scholar
  51. 51.
    Calabrese M, Filippi M, Gallo P (2010) Cortical lesion in multiple sclerosis. Nat Rev Neurol 6:438–444PubMedCrossRefGoogle Scholar
  52. 52.
    Kutzelnigg A, Lucchinetti CF, Stadelmann C et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712PubMedCrossRefGoogle Scholar
  53. 53.
    Peterson JW, Bø L, Mörk S et al (2001) Transected neuritis, apoptotic neurons and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400PubMedCrossRefGoogle Scholar
  54. 54.
    Bø L, Vedeler CA, Nyland H, Trapp BD, Mörk S (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 4:323–331CrossRefGoogle Scholar
  55. 55.
    van Horssen J, Brink BP, De Vries HE, van der Valk P, Bø L (2007) The blood-brain barrier in cortical multiple sclerosis lesions. J Neuropathol Exp Neurol 66:321–328PubMedCrossRefGoogle Scholar
  56. 56.
    Magliozzi R, Howell O, Vora A et al (2007) Meningeal B-cell follicles in secondary-progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104PubMedCrossRefGoogle Scholar
  57. 57.
    Kooi EJ, Geurts JJ, van Horssen J, Bø L, van der Valk P (2009) Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 68:1021–1028PubMedCrossRefGoogle Scholar
  58. 58.
    Dal Biancco A, Bradl M, Frischer J et al (2008) Multiple sclerosis and Alzheimer’s disease. Ann Neurol 63:174–183CrossRefGoogle Scholar
  59. 59.
    Magliozzi R, Howell OW, Reeves C et al (2010) A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 68:477–493PubMedCrossRefGoogle Scholar
  60. 60.
    Howell OW, Reeves CA, Nicholas R et al (2011) Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. doi: 10.1093/brain/awr182, advance access
  61. 61.
    Coles AJ, Compston DA, Selmaj KW et al (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359:1786–1801PubMedCrossRefGoogle Scholar
  62. 62.
    Naismith RT, Piccio L, Lyons JA et al (2010) Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology 74:1860–1867PubMedCrossRefGoogle Scholar
  63. 63.
    Kappos L, Radue EW, O’Connor P et al (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401PubMedCrossRefGoogle Scholar
  64. 64.
    Giovannoni G, Comi G, Cook S et al (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 362:416–426PubMedCrossRefGoogle Scholar
  65. 65.
    O’Connor PW, Li D, Freedman MS et al (2006) A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66:894–900PubMedCrossRefGoogle Scholar
  66. 66.
    O’Connor PW, Goodman A, Willmer-Hulme AJ et al (2004) Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology 62:2038–2043PubMedGoogle Scholar
  67. 67.
    Wynn D, Kaufmann M, Montalban X et al (2010) Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomized, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 9:381–390PubMedCrossRefGoogle Scholar
  68. 68.
    Comi G, Pulizzi A, Rovaris M et al (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371:2085–2092PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jin Nakahara
    • 1
    • 2
    • 3
  • Michiko Maeda
    • 2
    • 3
  • Sadakazu Aiso
    • 2
  • Norihiro Suzuki
    • 1
  1. 1.Department of NeurologyKeio University School of MedicineTokyoJapan
  2. 2.Department of AnatomyKeio University School of MedicineTokyoJapan
  3. 3.Center for Integrated Medical ResearchKeio University School of MedicineTokyoJapan

Personalised recommendations