Current Neurology and Neuroscience Reports

, Volume 9, Issue 5, pp 405–410 | Cite as

Epstein-barr virus in multiple sclerosis

Article

Abstract

Recent seroepidemiologic and pathologic evidence suggests that prior infection with Epstein-Barr virus (EBV) may be necessary for the development of multiple sclerosis (MS). EBV infects more than 90% of all humans, most of whom remain healthy. In contrast, 99% of MS patients have evidence of prior infection with EBV. EBV infects resting B lymphocytes, immortalizing them into long-lived memory B cells that survive largely undetected by the immune system in the peripheral circulation. MS patients show elevated titers to EBV years before developing any neurologic symptoms. Postmortem pathologic analysis of brains of patients with MS has revealed diffuse EBV-associated B-cell dysregulation in all forms of MS. Theories of pathogenesis of EBV in MS include antigenic mimicry, immortalization of B-cell clones, and cytotoxic T-cell dysfunction against virally infected B cells. This article reviews the existing evidence of the relationship between EBV and MS and considers the therapeutic implication of this evidence.

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References and Recommended Reading

  1. 1.
    Cohen JI: Epstein-Barr virus infection. N Engl J Med 2000, 343:481–492.PubMedCrossRefGoogle Scholar
  2. 2.
    Thorley-Lawson DA, Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004, 350:1328–1337.PubMedCrossRefGoogle Scholar
  3. 3.
    Levin LI, Munger KL, Rubertone MV, et al.: Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 2005, 293:2496–2500.PubMedCrossRefGoogle Scholar
  4. 4.
    Ascherio A, Munger KL, Lennette ET, et al.: Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001, 286:3083–3088.PubMedCrossRefGoogle Scholar
  5. 5.
    Levin LI, Munger KL, Rubertone MV, et al.: Multiple sclerosis and Epstein-Barr virus. JAMA 2003, 289:1533–1536.PubMedCrossRefGoogle Scholar
  6. 6.
    Serafini B, Rosicarelli B, Franciotta D, et al.: Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007, 204:2899–2912.PubMedCrossRefGoogle Scholar
  7. 7.
    Toussirot E, Roudier J: Epstein-Barr virus in autoimmune diseases. Best Pract Res Clin Rheumatol 2008, 22:883–896.PubMedCrossRefGoogle Scholar
  8. 8.
    Warner HB, Carp RI: Multiple sclerosis etiology—an Epstein-Barr virus hypothesis. Med Hypotheses 1988, 25:93–97.PubMedCrossRefGoogle Scholar
  9. 9.
    Operskalski EA, Visscher BR, Malmgren RM, et al.: A case-control study of multiple sclerosis. Neurology 1989, 39:825–829.PubMedGoogle Scholar
  10. 10.
    Thacker EL, Mirzaei F, Ascherio A: Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006, 59:499–503.PubMedCrossRefGoogle Scholar
  11. 11.
    Haahr S, Plesner AM, Vestergaard BF, et al.: A role of late Epstein-Barr virus infection in multiple sclerosis. Acta Neurol Scand 2004, 109:270–275.PubMedCrossRefGoogle Scholar
  12. 12.
    Hossain A: Seroepidemiology of Epstein-Barr virus infections in a developing country. J Trop Pediatr 1987, 33:257–260.PubMedGoogle Scholar
  13. 13.
    Sumaya CV, Myers LW, Ellison GW: Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 1980, 37:94–96.PubMedGoogle Scholar
  14. 14.
    Ascherio A, Munch M: Epstein-Barr virus and multiple sclerosis. Epidemiology 2000, 11:220–224.PubMedCrossRefGoogle Scholar
  15. 15.
    DeLorenze GN, Munger KL, Lennette ET, et al.: Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006, 63:839–844.PubMedCrossRefGoogle Scholar
  16. 16.
    Alotaibi S, Kennedy J, Tellier R, et al.: Epstein-Barr virus in pediatric multiple sclerosis. JAMA 2004, 291:1875–1879.PubMedCrossRefGoogle Scholar
  17. 17.
    Banwell B, Krupp L, Kennedy J, et al.: Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007, 6:773–781.PubMedCrossRefGoogle Scholar
  18. 18.
    Pohl D, Krone B, Rostasy K, et al.: High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 2006, 67:2063–2065.PubMedCrossRefGoogle Scholar
  19. 19.
    Lunemann JD, Huppke P, Roberts S, et al.: Broadened and elevated humoral immune response to EBNA1 in pediatric multiple sclerosis. Neurology 2008, 71:1033–1035.PubMedCrossRefGoogle Scholar
  20. 20.
    Serafini B, Rosicarelli B, Magliozzi R, et al.: Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004, 14:164–174.PubMedCrossRefGoogle Scholar
  21. 21.
    Lunemann JD, Jelcic I, Roberts S, et al.: EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J Exp Med 2008, 205:1763–1773.PubMedCrossRefGoogle Scholar
  22. 22.
    Holmoy T, Kvale EO, Vartdal F: Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein-Barr virus and myelin basic protein. J Neurovirol 2004, 10:278–283.PubMedCrossRefGoogle Scholar
  23. 23.
    Lang HL, Jacobsen H, Ikemizu S, et al.: A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002, 3:940–943.PubMedCrossRefGoogle Scholar
  24. 24.
    van Noort JM, Bajramovic JJ, Plomp AC, et al.: Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis. J Neuroimmunol 2000, 105:46–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Ousman SS, Tomooka BH, van Noort JM, et al.: Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 2007, 448:474–479.PubMedCrossRefGoogle Scholar
  26. 26.
    Bajramovic JJ, Plomp AC, Goes A, et al.: Presentation of alpha B-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory demyelination. J Immunol 2000, 164:4359–4366.PubMedGoogle Scholar
  27. 27.
    Chou YK, Burrows GG, LaTocha D, et al.: CD4 T-cell epitopes of human alpha B-crystallin. J Neurosci Res 2004, 75:516–523.PubMedCrossRefGoogle Scholar
  28. 28.
    van Sechel AC, Bajramovic JJ, van Stipdonk MJ, et al.: EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol 1999, 162:129–135.PubMedGoogle Scholar
  29. 29.
    Hauser SL, Waubant E, Arnold DL, et al.: B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008, 358:676–688.PubMedCrossRefGoogle Scholar
  30. 30.
    Fraser KB, Haire M, Millar JH, et al.: Increased tendency to spontaneous in-vitro lymphocyte transformation in clinically active multiple sclerosis. Lancet 1979, 2:175–176.PubMedGoogle Scholar
  31. 31.
    Kuenz B, Lutterotti A, Ehling R, et al.: Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis. PLoS ONE 2008, 3:e2559.PubMedCrossRefGoogle Scholar
  32. 32.
    Jarius S, Eichhorn P, Jacobi C, et al.: The intrathecal, polyspecific antiviral immune response: specific for MS or a general marker of CNS autoimmunity? J Neurol Sci 2009, 280:98–100.PubMedCrossRefGoogle Scholar
  33. 33.
    Franciotta D, Salvetti M, Lolli F, et al.: B cells and multiple sclerosis. Lancet Neurol 2008, 7:852–858.PubMedCrossRefGoogle Scholar
  34. 34.
    Pender MP: Preventing and curing multiple sclerosis by controlling Epstein-Barr virus infection. Autoimmun Rev 2009, 8:563–568.PubMedCrossRefGoogle Scholar
  35. 35.
    Pender MP, Csurhes PA, Lenarczyk A, et al.: Decreased T-cell reactivity to Epstein-Barr virus-infected lymphoblastoid cell lines in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009, 80:498–505.PubMedCrossRefGoogle Scholar
  36. 36.
    Craig JC, Haire M, Merrett JD: T-cell-mediated suppression of Epstein-Barr virus-induced B lymphocyte activation in multiple sclerosis. Clin Immunol Immunopathol 1988, 48:253–260.PubMedCrossRefGoogle Scholar
  37. 37.
    Jilek S, Schluep M, Meylan P, et al.: Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 2008, 131(Pt 7):1712–1721.PubMedCrossRefGoogle Scholar
  38. 38.
    Krone B, Oeffner F, Grange JM: Is the risk of multiple sclerosis related to the ‘biography’ of the immune system? J Neurol 2009 Mar 1 (Epub ahead of print).Google Scholar
  39. 39.
    Hollsberg P, Kusk M, Bech E, et al.: Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand 2005, 112:395–402.PubMedCrossRefGoogle Scholar
  40. 40.
    Wagner HJ, Munger KL, Ascherio A: Plasma viral load of Epstein-Barr virus and risk of multiple sclerosis. Eur J Neurol 2004, 11:833–834.PubMedCrossRefGoogle Scholar
  41. 41.
    Wandinger K, Jabs W, Siekhaus A, et al.: Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000, 55:178–184.PubMedGoogle Scholar
  42. 42.
    Zivadinov R, Zorzon M, Weinstock-Guttman B, et al.: Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009, 80:620–625.PubMedCrossRefGoogle Scholar
  43. 43.
    Munger KL, Levin LI, Hollis BW, et al.: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006, 296:2832–2838.PubMedCrossRefGoogle Scholar
  44. 44.
    Munger KL, Zhang SM, O’Reilly E, et al.: Vitamin D intake and incidence of multiple sclerosis. Neurology 2004, 62:60–65.PubMedGoogle Scholar
  45. 45.
    Brennan A, Katz DR, Nunn JD, et al.: Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology 1987, 61:457–461.PubMedGoogle Scholar
  46. 46.
    Provvedini DM, Tsoukas CD, Deftos LJ, et al.: 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983, 221:1181–1183.PubMedCrossRefGoogle Scholar
  47. 47.
    Tsoukas CD, Provvedini DM, Manolagas SC: 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 1984, 224:1438–1440.PubMedCrossRefGoogle Scholar
  48. 48.
    Jordan SC, Toyoda M, Prehn J, et al.: 1,25-dihydroxyvitamin-D3 regulation of interleukin-2 and interleukin-2 receptor levels and gene expression in human T cells. Mol Immunol 1989, 26:979–984.PubMedCrossRefGoogle Scholar
  49. 49.
    Penna G, Giarratana N, Amuchastegui S, et al.: Manipulating dendritic cells to induce regulatory T cells. Microbes Infect 2005, 7:1033–1039.PubMedCrossRefGoogle Scholar
  50. 50.
    Holmoy T: Vitamin D status modulates the immune response to Epstein Barr virus: synergistic effect of risk factors in multiple sclerosis. Med Hypotheses 2008, 70:66–69.PubMedCrossRefGoogle Scholar
  51. 51.
    De Jager PL, Simon KC, Munger KL, et al.: Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology 2008, 70(13 Pt 2):1113–1118.PubMedGoogle Scholar
  52. 52.
    Sundstrom P, Nystrom L, Jidell E, et al.: EBNA-1 reactivity and HLA DRB1*1501 as statistically independent risk factors for multiple sclerosis: a case-control study. Mult Scler 2008, 14:1120–1122.PubMedCrossRefGoogle Scholar
  53. 53.
    Nielsen T, Rostgaard K, Askling J, et al.: Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Mult Scler 2009, 15:431–436.PubMedCrossRefGoogle Scholar
  54. 54.
    Yasui Y, Hamajima N, Nakamura T, et al.: Association of Epstein-Barr virus antibody titers with a human IL-10 promoter polymorphism in Japanese women. J Autoimmune Dis 2008, 5:2.PubMedCrossRefGoogle Scholar
  55. 55.
    Hafler DA, Compston A, Sawcer S, et al.: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007, 357:851–862.PubMedCrossRefGoogle Scholar
  56. 56.
    Tai AK, O’Reilly EJ, Alroy KA, et al.: Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis. Mult Scler 2008, 14:1175–1180.PubMedCrossRefGoogle Scholar
  57. 57.
    Ascherio A: Epstein-Barr virus in the development of multiple sclerosis. Expert Rev Neurother 2008, 8:331–333.PubMedCrossRefGoogle Scholar
  58. 58.
    Lockey TD, Zhan X, Surman S, et al.: Epstein-Barr virus vaccine development: a lytic and latent protein cocktail. Front Biosci 2008, 13:5916–5927.PubMedCrossRefGoogle Scholar
  59. 59.
    Williams H, Crawford DH, Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood 2006, 107:862–869.PubMedCrossRefGoogle Scholar
  60. 60.
    Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al.: Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis 2007, 196:1749–1753.PubMedCrossRefGoogle Scholar
  61. 61.
    Lassmann H: New concepts on progressive multiple sclerosis. Curr Neurol Neurosci Rep 2007, 7:239–244.PubMedCrossRefGoogle Scholar
  62. 62.
    Bech E, Lycke J, Gadeberg P, et al.: A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 2002, 58:31–36.PubMedGoogle Scholar
  63. 63.
    Friedman JE, Zabriskie JB, Plank C, et al.: A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler 2005, 11:286–295.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Department of NeurologyLouisiana State University Health Science CenterNew OrleansUSA

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