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Epstein-Barr virus and multiple sclerosis

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Abstract

Epstein-Barr virus (EBV) is one of the most common and successful human viruses, infecting more than 90% of the world’s adult population. Despite its strong tumorigenic potential, most virus carriers remain healthy due to maintenance of a delicate balance between the host’s immune system, which limits production of virus particles, and the virus, which persists for the duration of the host’s life. New data show that this balance is altered on a subtle level in patients with multiple sclerosis (MS) and other autoimmune diseases who show enhanced as well as less restricted T-cell and antibody responses to EBV-encoded antigens. Such quantitatively and qualitatively distinct immune responses and the virus’ unique ability to immortalize B cells as well as to continuously stimulate strong T-cell responses during persistent infection suggest a possible role for EBV in the initiation and progression of symptomatic autoimmunity. We hypothesize that EBV promotes both autoimmune B and T-cell responses. EBV gene products might stimulate cross-reactive autoimmune B cells directly or increase their survival after infection. In addition, autoimmune T cells could be maintained via molecular mimicry between autoantigens and EBV antigens, and via the Th1 polarizing cytokine milieu of protective antiviral T-cell immunity. A better understanding of how EBV and EBV-specific immune control mechanisms interfere with the evolution of autoimmunity may generate a rationale for novel EBV-targeting therapeutic strategies aimed at the prevention and more efficient treatment of autoimmune diseases.

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References and Recommended Reading

  1. Sospedra M, Martin R: Immunology of multiple sclerosis. Annu Rev Immunol 2005, 23:683–747.

    Article  PubMed  CAS  Google Scholar 

  2. Kurtzke JF: Epidemiology and etiology of multiple sclerosis. Phys Med Rehabil Clin North Am 2005, 16:327–349.

    Google Scholar 

  3. Sibley WA, Bamford CR, Clark K: Clinical viral infections and multiple sclerosis. Lancet 1985, 1:1313–1315.

    Article  PubMed  CAS  Google Scholar 

  4. Khan G, Miyashita EM, Yang B, et al.: Is EBV persistence in vivo a model for B cell homeostasis? Immunity 1996, 5:173–179.

    Article  PubMed  CAS  Google Scholar 

  5. Callan MF, Annels N, Steven N, et al.: T cell selection during the evolution of CD8+ T cell memory in vivo. Eur J Immunol 1998, 28:4382–4390.

    Article  PubMed  CAS  Google Scholar 

  6. Callan MF, Tan L, Annels N, et al.: Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 1998, 187:1395–1402.

    Article  PubMed  CAS  Google Scholar 

  7. Tan LC, Gudgeon N, Annels NE, et al.: A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol 1999, 162:1827–1835.

    PubMed  CAS  Google Scholar 

  8. Tan LC, Gudgeon N, Annels NE, et al.: A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol 1999, 162:1827–1835.

    PubMed  CAS  Google Scholar 

  9. Schoenberger SP, Toes RE, van der Voort EI, et al.: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998, 393:480–483.

    Article  PubMed  CAS  Google Scholar 

  10. Bennett SR, Carbone FR, Karamalis F, et al.: Help for cytotoxic-T-cell responses is mediated by CD40 signalling [see comments]. Nature 1998, 393:478–480.

    Article  PubMed  CAS  Google Scholar 

  11. Schoenberger SP, Toes RE, van der Voort EI, et al.: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions [see comments]. Nature 1998, 393:480–483.

    Article  PubMed  CAS  Google Scholar 

  12. Ridge JP, Di Rosa F, Matzinger P: A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell [see comments]. Nature 1998, 393:474–478.

    Article  PubMed  CAS  Google Scholar 

  13. Cardin RD, Brooks JW, Sarawar SR, Doherty PC: Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J Exp Med 1996, 184:863–871.

    Article  PubMed  CAS  Google Scholar 

  14. Zajac AJ, Blattman JN, Murali-Krishna K, et al.: Viral immune evasion due to persistence of activated T cells without effector function [see comments]. J Exp Med 1998, 188:2205–2213.

    Article  PubMed  CAS  Google Scholar 

  15. Paludan C, Bickham K, Nikiforow S, et al.: Epstein-Barr nuclear antigen 1-specific CD4(+) Th1 cells kill Burkitt’s lymphoma cells. J Immunol 2002, 169:1593–1603.

    PubMed  CAS  Google Scholar 

  16. Paludan C, Schmid D, Landthaler M, et al.: Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 2005, 307:593–596.

    Article  PubMed  CAS  Google Scholar 

  17. Evans AS: The spectrum of infections with Epstein-Barr virus: a hypothesis. J Infect Dis 1971, 124:330–337.

    PubMed  CAS  Google Scholar 

  18. Operskalski EA, Visscher BR, Malmgren RM, Detels R: A case-control study of multiple sclerosis. Neurology 1989, 39:825–829.

    PubMed  CAS  Google Scholar 

  19. Lindberg C, Andersen O, Vahlne A, et al.: Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Neuroepidemiology 1991, 10:62–65.

    PubMed  CAS  Google Scholar 

  20. Thacker EL, Mirzaei F, Ascherio A: Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006, 59:499–503.

    Article  PubMed  Google Scholar 

  21. Hjalgrim H, Askling J, Rostgaard K, et al.: Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 2003, 349:1324–1332.

    Article  PubMed  CAS  Google Scholar 

  22. Alotaibi S, Kennedy J, Tellier R, et al.: Epstein-Barr virus in pediatric multiple sclerosis. JAMA 2004, 291:1875–1879.

    Article  PubMed  CAS  Google Scholar 

  23. Pohl D, Krone B, Rostasy K, et al.: High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 2006, 67:2063–2065.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. Sundstrom P, Juto P, Wadell G, et al.: An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 2004, 62:2277–2282.

    PubMed  CAS  Google Scholar 

  28. Thorley-Lawson DA: Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 2001, 1:75–82.

    Article  PubMed  CAS  Google Scholar 

  29. Rickinson AB, Moss DJ: Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol 1997, 15:405–431.

    Article  PubMed  CAS  Google Scholar 

  30. Cohen JI. Epstein-Barr virus infection. N Engl J Med 2000, 343:481–492.

    Article  PubMed  CAS  Google Scholar 

  31. Williams H, Crawford DH: Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood 2006, 107:862–869.

    Article  PubMed  CAS  Google Scholar 

  32. Colombo M, Dono M, Gazzola P, et al.: Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol 2000, 164:2782–2789.

    PubMed  CAS  Google Scholar 

  33. Colombo M, Dono M, Gazzola P, et al.: Maintenance of B lymphocyte-related clones in the cerebrospinal fluid of multiple sclerosis patients. Eur J Immunol 2003, 33:3433–3438.

    Article  PubMed  CAS  Google Scholar 

  34. Cepok S, Zhou D, Srivastava R, et al.: Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005, 115:1352–1360.

    Article  PubMed  CAS  Google Scholar 

  35. Bray PF, Luka J, Culp KW, Schlight JP: Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 1992, 42:1798–1804.

    PubMed  CAS  Google Scholar 

  36. Wucherpfennig KW, Strominger JL: Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995, 80:695–705.

    Article  PubMed  CAS  Google Scholar 

  37. Lang HL, Jacobsen H, Ikemizu S, et al.: A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002, 10:940–943.

    Article  Google Scholar 

  38. Lunemann JD, Edwards N, Muraro PA, et al.: Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 2006, 129(Pt 6):1493–1506.

    Article  PubMed  Google Scholar 

  39. Gronen F, Ruprecht K, Weissbrich B, et al.: Frequency analysis of HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol 2006, 180(1–2):185–192.

    Article  PubMed  CAS  Google Scholar 

  40. Antony JM, van Marle G, Opii W, et al.: Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 2004, 7:1088–1095.

    Article  PubMed  CAS  Google Scholar 

  41. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R: Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 1998, 9:405–411.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, Box 390, 1230 York Avenue, New York, NY, 10021-6399, USA

    Jan D. Lünemann MD

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  1. Jan D. Lünemann MD
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  2. Christian Münz PhD
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Correspondence to Jan D. Lünemann MD.

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Lünemann, J.D., Münz, C. Epstein-Barr virus and multiple sclerosis. Curr Neurol Neurosci Rep 7, 253–258 (2007). https://doi.org/10.1007/s11910-007-0038-y

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