Journal of NeuroVirology

, Volume 10, Issue 5, pp 278–283 | Cite as

Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein-Barr virus and myelin basic protein

  • Trygve Holmøy
  • Espen Østhagen Kvale
  • Frode Vartdal
Article

Abstract

Epstein-Barr virus-specific CD4+ T cells could be involved in the pathogenesis of multiple sclerosis, provided they can gain entry to the intrathecal compartment. The authors have previously demonstrated that cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. They now report that CD4+ T cells specific for the Epstein-Barr virus DNA polymerase peptide EBV 627–641 were present in the cerebrospinal fluid from one of two multiple sclerosis patients, and that a high proportion of these CD4+ T cells cross-recognized an immunodominant myelin basic protein peptide, MBP 85–99. In the observed patient, the proportion of EBV 627–641-specific CD4+ T cells seemed to exceed 1/10 000 in cerebrospinal fluid, compared to approximately 1/100 000 in blood. These findings prove that Epstein-Barr-virus specific CD4+ T cells can gain access to the intrathecal compartment, and suggest that Epstein-Barr virus-specific CD4+ T cells could target myelin basic protein in the central nervous system.

Keywords

cerebrospinal fluid Epstein-Barr virus multiple sclerosis myelin basic protein specificity T cells 

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References

  1. Amyes E, Hatton C, Montamat-Sicotte D, Gudgeon N, Rickinson AB, McMichael AJ, Callan MF (2003). Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection. J Exp Med 198: 903–911.CrossRefPubMedGoogle Scholar
  2. Ascherio A, Munch M (2000). Epstein-Barr virus and multiple sclerosis. Epidemiology 11: 220–224.CrossRefPubMedGoogle Scholar
  3. Cepok S, Jacobsen M, Schock S, Omer B, Jaekel S, Boddeker I, Oertel WH, Sommer N, Hemmer B (2001). Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 124: 2169–2176.CrossRefPubMedGoogle Scholar
  4. Ebers GC, Sadovnick AD, Risch NJ (1995). A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 377: 150–151.CrossRefPubMedGoogle Scholar
  5. Fazekas de St Groth S (1982). The evaluation of limiting dilution assays (1982). J Immunol Methods 49: R11-R23.CrossRefPubMedGoogle Scholar
  6. Fitch FW, Gajewski TF (1997). In vitro assays for mouse lymphocyte function. In Current protocols in immunology. Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W (eds). New York: John Wiley & Sons, pp 3.13.1–3.13.14.Google Scholar
  7. Furnari FB, Adams MD, Pagano JS (1992). Regulation of the Epstein-Barr virus DNA polymerase gene. J Virol 66: 2837–2845.PubMedGoogle Scholar
  8. Gaudernack G, Lundin KE (1989). Rapid immunomagnetic phenotyping of cells. J Immunogenet 16: 169–175.CrossRefPubMedGoogle Scholar
  9. Gedde-Dahl T 3rd, Eriksen JA, Thorsby E, Gaudernack G (1992). T-cell responses against products of oncogenes: generation and characterization of human T-cell clones specific for p21 ras-derived synthetic peptides. Human Immunol 33: 266–274.CrossRefGoogle Scholar
  10. Haahr S, Koch-Henriksen N, Moller-Larsen A, Eriksen LS, Andersen HM (1995). Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study. Mult Scler 1: 73–77.PubMedGoogle Scholar
  11. Hickey WF, Hsu BL, Kimura H (1991). T-lymphocyte entry into the central nervous system. J Neurosci Res 28: 254–260.CrossRefPubMedGoogle Scholar
  12. Holmøy T, Vartdal F (2004). Cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. J NeuroVirol 10: 52–56.CrossRefPubMedGoogle Scholar
  13. Holmøy T, Vartdal F, Vandvik B (2003). T cells from multiple sclerosis patients recognize immunoglobulin G from autologous cerebrospinal fluid. Mult Scler 9: 228–234.CrossRefPubMedGoogle Scholar
  14. Ishigami T, White CA, Pender P (1998). Soluble antigen therapy induces apoptosis of autoreactive T cells preferentially in the target organ rather than in the peripheral lymphoid organs. Eur J Immunol 28: 1626–1635.CrossRefPubMedGoogle Scholar
  15. Kurtzke JF (2000). Multiple sclerosis in time and space-geographic clues to cause. J NeuroVirol 6(Suppl 2): 134–140.Google Scholar
  16. Lang H, Jacobsen LH, Ikemizu S, Andersson C, Harlos K, Madsen L, Hjorth P, Sondergaard L, Svejgaard A, Wucherpfennig K, Stuart DI, Bell JI, Jones EY, Fugger L (2002). A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 3: 940–943.CrossRefPubMedGoogle Scholar
  17. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2003). Multiple sclerosis and Epstein-Barr virus. JAMA 289: 1533–1536.CrossRefPubMedGoogle Scholar
  18. Li Pira G, Oppezzi L, Seri M, Westby M, Caroli F, Fenoglio D, Lancia F, Ferraris A, Bottone L, Valle MT, Kunkl A, Romeo G, Dalgleish AG, Manca F (1999). Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary antigens) or for PPD and tetanus toxoid (secondary antigens). Hum Immunol 59: 137–148.CrossRefGoogle Scholar
  19. Martyn CN, Cruddas M, Compston DA (1993). Symptomatic Epstein-Barr virus infection and multiple sclerosis. J Neurol Neurosurg Psychiatry 56: 167–168.CrossRefPubMedGoogle Scholar
  20. Mason D (1988). A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19: 395–404.CrossRefGoogle Scholar
  21. Morre SA, van Beek J, De Groot CJ, Killestein J, Meijer CJ, Polman CH, van der Valk P, Middeldorp JM, van Den Brule AJ (2001). Is Epstein-Barr virus present in the CNS of patients with MS? Neurology 56: 692.PubMedGoogle Scholar
  22. Munch M, Hvas J, Christensen T, Moller-Larsen A, Haahr S (1998). A single subtype of Epstein-Barr virus in members of multiple sclerosis clusters. Acta Neurol Scand 98: 395–399.CrossRefPubMedGoogle Scholar
  23. Oldstone MB (1987). Molecular mimicry and autoimmune disease. Cell 50: 819–820.CrossRefPubMedGoogle Scholar
  24. Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA (1990). T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346: 183–187.CrossRefPubMedGoogle Scholar
  25. Pender MP, Csurhes PA, Greer JM, Mowat PD, Henderson RD, Cameron KD, Purdie DM, McCombe PA, Good MF (2000). Surges of increased T cell reactivity to an encephalitogenic region of myelin proteolipid protein occur more often in patients with multiple sclerosis than in healthy subjects. J Neuroimmunol 165: 5322–5311.Google Scholar
  26. Selin LK, Varga SM, Wong IC, Welsh RM (1998). Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J Exp Med 188: 1705–1715.CrossRefPubMedGoogle Scholar
  27. Tejada-Simon MV, Zang YC, Hong J, Rivera M, Zhang JZ (2003). Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol 53: 189–197.CrossRefPubMedGoogle Scholar
  28. Thorley-Lawson (2001). Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1: 75–82.CrossRefPubMedGoogle Scholar
  29. Wucherpfennig KW, Strominger JL (1995). Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80: 695–705.CrossRefPubMedGoogle Scholar
  30. Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA (1994). Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 179: 973–984.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2004

Authors and Affiliations

  • Trygve Holmøy
    • 1
  • Espen Østhagen Kvale
    • 1
  • Frode Vartdal
    • 1
  1. 1.Institute of ImmunologyRikshospitalet University HospitalOsloNorway

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