Journal of Neuroimmune Pharmacology

, Volume 5, Issue 3, pp 271–277 | Cite as

Epstein–Barr Virus Infection and Multiple Sclerosis: A Review

BRIEF REPORT

Abstract

Epstein–Barr virus (EBV) infection results in a life-long persistence of the virus in the host’s B-lymphocytes and has been associated with numerous cancers including Burkitt’s lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. There is considerable evidence that EBV infection is a strong risk factor for the development of multiple sclerosis. Early age at primary EBV infection is typically asymptomatic, but primary infection during adolescence or adulthood often manifests as infectious mononucleosis, which has been associated with a two- to threefold increased risk of MS. Most importantly, MS risk is extremely low in individuals who are EBV negative, but it increases several folds following EBV infection. Additional evidence supporting a role for EBV in MS pathogenesis includes the observations of elevated antibodies to EBV antigens (especially EBV nuclear antigen-1) prior to the onset of MS, and an increased risk of MS among EBV-positive children. The biological mechanism by which EBV may cause MS is not known, but several possibilities are discussed.

Keywords

Epstein–Barr virus multiple sclerosis infection 

References

  1. Ahlgren C et al (2009) A population-based case–control study on viral infections and vaccinations and subsequent multiple sclerosis risk. Eur J Epidemiol 24(9):541–552CrossRefPubMedGoogle Scholar
  2. Alotaibi S et al (2004) Epstein–Barr virus in pediatric multiple sclerosis. JAMA 291(15):1875–1879CrossRefPubMedGoogle Scholar
  3. Ascherio A, Munger KL (2007a) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61(4):288–299CrossRefPubMedGoogle Scholar
  4. Ascherio A, Munger KL (2007b) Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 61(6):504–513CrossRefPubMedGoogle Scholar
  5. Ascherio A, Munger KL (2010) Epidemiology of multiple sclerosis: environmental factors, In: Luchinetti and Hohlfeld, eds. Multiple Sclerosis 3, 1st ed. Philadelphia: Saunders, Elsevier 57–82. Copyright © 2010 Elsevier. All rights reservedGoogle Scholar
  6. Ascherio A et al (2001) Epstein–barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286(24):3083–3088CrossRefPubMedGoogle Scholar
  7. Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347(12):911–920CrossRefPubMedGoogle Scholar
  8. Banwell B et al (2007) Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 6(9):773–781CrossRefPubMedGoogle Scholar
  9. Bech E et al (2002) A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 58(1):31–36PubMedGoogle Scholar
  10. Buljevac D et al (2005) Epstein–Barr virus and disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 76(10):1377–1381CrossRefPubMedGoogle Scholar
  11. Cepok S et al (2005) Identification of Epstein–Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115(5):1352–1360PubMedGoogle Scholar
  12. Chang ET, Adami HO (2006) The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 15(10):1765–1777CrossRefPubMedGoogle Scholar
  13. Clute SC et al (2005) Cross-reactive influenza virus-specific CD8 T cells contribute to lymphoproliferation in Epstein–Barr virus-associated infectious mononucleosis. J Clin Invest 115(12):3602–3612CrossRefPubMedGoogle Scholar
  14. De Jager PL et al (2008) Integrating risk factors: HLA-DRB1*1501 and Epstein–Barr virus in multiple sclerosis. Neurology 70(13 Pt 2):1113–1118PubMedGoogle Scholar
  15. DeLorenze GN et al (2006) Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63(6):839–844CrossRefPubMedGoogle Scholar
  16. Ebers GC et al (1995) A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 377(6545):150–151CrossRefPubMedGoogle Scholar
  17. Farrell RA et al (2009) Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology 73(1):32–38CrossRefPubMedGoogle Scholar
  18. Feng BJ et al (2007) Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries. Int J Cancer 121(7):1550–1555CrossRefPubMedGoogle Scholar
  19. Friedman JE et al (2005) A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler 11(3):286–295CrossRefPubMedGoogle Scholar
  20. Gale CR, Martyn CN (1995) Migrant studies in multiple sclerosis. Prog Neurobiol 47:425–448CrossRefPubMedGoogle Scholar
  21. Gratama JW, Ernberg I (1995) Molecular epidemiology of Epstein–Barr virus infection. Adv Cancer Res 67:197–255CrossRefPubMedGoogle Scholar
  22. Gronen F et al (2006) Frequency analysis of HLA-B7-restricted Epstein–Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol 180(1–2):185–192CrossRefPubMedGoogle Scholar
  23. Hauser SL et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358(7):676–688CrossRefPubMedGoogle Scholar
  24. Hjalgrim H et al (2003) Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349(14):1324–1332CrossRefPubMedGoogle Scholar
  25. Hollsberg P et al (2003) Altered CD8+T cell responses to selected Epstein–Barr virus immunodominant epitopes in patients with multiple sclerosis. Clin Exp Immunol 132:137–143CrossRefPubMedGoogle Scholar
  26. Holmoy T et al (2004) Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein–Barr virus and myelin basic protein. J Neurovirology 10(5):278–283CrossRefGoogle Scholar
  27. Iwakiri D et al (2009) Epstein–Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. J Exp Med 206(10):2091–2099CrossRefPubMedGoogle Scholar
  28. Jilek S et al (2008) Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 131(Pt 7):1712–1721CrossRefPubMedGoogle Scholar
  29. Kieff ED, Rickinson AB (2007) Epstein–Barr virus and its replication. In: Knipe DM et al (eds) Fields virology, vol 2, 5th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, pp 2603–2654Google Scholar
  30. Kim SK et al (2005) Private specificities of CD8 T cell responses control patterns of heterologous immunity. J Exp Med 201(4):523–533CrossRefPubMedGoogle Scholar
  31. Kurtzke JF, Heltberg A (2001) Multiple sclerosis in the Faroe Islands: an epitome. J Clin Epidemiol 54(1):1–22CrossRefPubMedGoogle Scholar
  32. Kutok JL, Wang F (2006) Spectrum of Epstein–Barr virus-associated diseases. Annu Rev Pathol 1:375–404CrossRefPubMedGoogle Scholar
  33. Lang HL et al (2002) A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 3(10):940–943CrossRefPubMedGoogle Scholar
  34. Levin LI et al (2005) Temporal relationship between elevation of Epstein Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293(20):2496–2500CrossRefPubMedGoogle Scholar
  35. Levin LI et al (2010) Primary infection with the Epstein–Barr virus and risk of multiple sclerosis. Ann Neurol. doi:10.1002/ana.21978
  36. Lindsey JW et al (2008) Epstein–Barr virus genotypes in multiple sclerosis. Acta Neurol Scand 117(2):141–144PubMedGoogle Scholar
  37. Lunemann JD et al (2006) Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129(Pt 6):1493–1506CrossRefPubMedGoogle Scholar
  38. Lunemann JD et al (2008) 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 205(8):1763–1773CrossRefPubMedGoogle Scholar
  39. Lycke J et al (1996) Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol 243:214–224CrossRefPubMedGoogle Scholar
  40. Massa J et al (2007) Plasma titers of antibodies against Epstein–Barr virus BZLF1 and risk of multiple sclerosis. Neuroepidemiology 28(4):214–215CrossRefPubMedGoogle Scholar
  41. Melbye M et al (1984) Early primary infection and high Epstein–Barr virus antibody titers in Greenland Eskimos at high risk for nasopharyngeal carcinoma. Int J Cancer 34:619–623CrossRefPubMedGoogle Scholar
  42. Moormann AM et al (2007) Exposure to holoendemic malaria results in suppression of Epstein–Barr virus-specific T cell immunosurveillance in kenyan children. J Infect Dis 195(6):799–808CrossRefPubMedGoogle Scholar
  43. Moutschen M et al (2007) Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein–Barr virus vaccine in healthy adults. Vaccine 25(24):4697–4705CrossRefPubMedGoogle Scholar
  44. Munch M et al (1998) A single subtype of Epstein–Barr virus in members of multiple sclerosis clusters. Acta Neurol Scand 98:395–399CrossRefPubMedGoogle Scholar
  45. Munger KL et al (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62:60–65PubMedGoogle Scholar
  46. Munger KL et al (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23):2832–2838CrossRefPubMedGoogle Scholar
  47. Nielsen TR et al (2007) Multiple sclerosis after infectious mononucleosis. Arch Neurol 64(1):72–75CrossRefPubMedGoogle Scholar
  48. Peferoen LA et al (2009) Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain. doi:10.1093/brain/awp296
  49. Pender MP (2003) Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 24(11):584–588CrossRefPubMedGoogle Scholar
  50. Pender MP et al (2009) Decreased T-cell reactivity to Epstein–Barr virus-infected lymphoblastoid cell lines in multiple sclerosis. J Neurol Neurosurg Psychiatry 80(5):498–505CrossRefPubMedGoogle Scholar
  51. Pohl D et al (2006) High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67(11):2063–2065CrossRefPubMedGoogle Scholar
  52. Ramagopalan SV et al (2009) Association of infectious mononucleosis with multiple sclerosis. A population-based study. Neuroepidemiology 32(4):257–262CrossRefPubMedGoogle Scholar
  53. Rand KH et al (2000) Epstein–Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173(1):32–39CrossRefPubMedGoogle Scholar
  54. Rickinson AB, Kieff E (2007) Epstein–Barr virus. In: Knipe DM et al (eds) Fields virology, vol 2, 5th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, pp 2655–2700Google Scholar
  55. Rowe M et al (2009) Burkitt's lymphoma: the rosetta stone deciphering Epstein–Barr virus biology. Semin Cancer Biol 19(6):377–388CrossRefPubMedGoogle Scholar
  56. Sargsyan SA et al (2010) Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. doi:10.1212/WNL.0b013e3181d865a1
  57. Serafini B et al (2007) Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J Exp Med 204(12):2899–2912CrossRefPubMedGoogle Scholar
  58. Simon KC et al (2007) Variation in the Epstein–Barr virus receptor, CR2, and risk of multiple sclerosis. Mult Scler 13(7):947–948CrossRefPubMedGoogle Scholar
  59. Sokal EM et al (2007) 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 196(12):1749–1753CrossRefPubMedGoogle Scholar
  60. Sundstrom P et al (2004) An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62(12):2277–2282PubMedGoogle Scholar
  61. Sutkowski N et al (2001) Epstein–Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity 15(4):579–589CrossRefPubMedGoogle Scholar
  62. Tai A et al (2008) Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis. Mult Scler 14(9):1175–1180CrossRefPubMedGoogle Scholar
  63. Takeuchi K et al (2006) Prevalence of Epstein–Barr virus in Japan: trends and future prediction. Pathol Int 56(3):112–116CrossRefPubMedGoogle Scholar
  64. Thacker EL et al (2006) Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 59(3):499–503CrossRefPubMedGoogle Scholar
  65. Thorley-Lawson DA (2001) Epstein–Barr virus: exploiting the immune system. Nat Rev Immunol 1(1):75–82CrossRefPubMedGoogle Scholar
  66. van Sechel AC et al (1999) EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol 162(1):129–135PubMedGoogle Scholar
  67. Vaughn JH et al (1996) An Epstein–Barr virus-related cross reactive autoimmune response in multiple sclerosis in Norway. J Neuroimmunol 69:95–102CrossRefGoogle Scholar
  68. Wagner H-J et al (2004) Plasma viral load of Epstein–Barr virus and risk of multiple sclerosis. Eur J Neurol 11:833–834CrossRefPubMedGoogle Scholar
  69. Wandinger K et al (2000) Association between clinical disease activity and Epstein–Barr virus reactivation in MS. Neurology 55(2):178–184PubMedGoogle Scholar
  70. Warner HB, Carp RI (1981) Multiple sclerosis and Epstein–Barr virus (letter). Lancet 2:1290CrossRefPubMedGoogle Scholar
  71. Willis SN et al (2009) Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132(Pt 12):3318–3328CrossRefPubMedGoogle Scholar
  72. Zaadstra BM et al (2008) Selective association of multiple sclerosis with infectious mononucleosis. Mult Scler 14(3):307–313CrossRefPubMedGoogle Scholar
  73. Zivadinov R et al (2009) Epstein–Barr Virus is associated with gray matter atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 80(6):620–625CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of NutritionHarvard School of Public HealthBostonUSA
  2. 2.Department of EpidemiologyHarvard School of Public HealthBostonUSA

Personalised recommendations