Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Nov 1;184(5):1791–1800. doi: 10.1084/jem.184.5.1791

T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis

PMCID: PMC2192863  PMID: 8920867

Abstract

Rheumatoid arthritis is a multistep disorder associated with autoimmune features of yet unknown etiology. Implication of viruses such as Epstein-Barr virus (EBV) in rheumatoid arthritis pathogenesis has been suspected on the basis of several indirect observations, but thus far, a direct link between EBV and rheumatoid arthritis has not been provided. Here we show that a large fraction of T cells infiltrating affected joints from a patient with chronic rheumatoid arthritis recognizes two EBV transactivators (BZLF1 and BMLF1) in a major histocompatibility complex-restricted fashion. Responses to these EBV antigens by synovial lymphocytes from several other chronic rheumatoid arthritis patients were readily detectable. Thus these results suggest a direct contribution of EBV to chronic rheumatoid arthritis pathogenesis. They also demonstrate for the first time the occurrence of T cell responses against EBV transactivating factors, which might be central in the control of virus reactivation.

Full Text

The Full Text of this article is available as a PDF (738.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alspaugh M. A., Henle G., Lennette E. T., Henle W. Elevated levels of antibodies to Epstein-Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis. J Clin Invest. 1981 Apr;67(4):1134–1140. doi: 10.1172/JCI110127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Bardwick P. A., Bluestein H. G., Zvaifler N. J., Depper J. M., Seegmiller J. E. Altered regulation of Epstein-Barr virus induced lymphoblast proliferation in rheumatoid arthritis lymphoid cells. Arthritis Rheum. 1980 Jun;23(6):626–632. doi: 10.1002/art.1780230603. [DOI] [PubMed] [Google Scholar]
  4. Brichard V., Van Pel A., Wölfel T., Wölfel C., De Plaen E., Lethé B., Coulie P., Boon T. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1993 Aug 1;178(2):489–495. doi: 10.1084/jem.178.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brousset P., Caulier M., Cantagrel A., Dromer C., Mazières B., Delsol G. Absence of Epstein-Barr virus carrying cells in synovial membranes and subcutaneous nodules of patients with rheumatoid arthritis. Ann Rheum Dis. 1993 Aug;52(8):608–609. doi: 10.1136/ard.52.8.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chevallier-Greco A., Manet E., Chavrier P., Mosnier C., Daillie J., Sergeant A. Both Epstein-Barr virus (EBV)-encoded trans-acting factors, EB1 and EB2, are required to activate transcription from an EBV early promoter. EMBO J. 1986 Dec 1;5(12):3243–3249. doi: 10.1002/j.1460-2075.1986.tb04635.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  8. Firestein G. S., Zvaifler N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990 Jun;33(6):768–773. doi: 10.1002/art.1780330602. [DOI] [PubMed] [Google Scholar]
  9. Fox R. I., Luppi M., Pisa P., Kang H. I. Potential role of Epstein-Barr virus in Sjögren's syndrome and rheumatoid arthritis. J Rheumatol Suppl. 1992 Jan;32:18–24. [PubMed] [Google Scholar]
  10. Fox R., Sportsman R., Rhodes G., Luka J., Pearson G., Vaughan J. Rheumatoid arthritis synovial membrane contains a 62,000-molecular-weight protein that shares an antigenic epitope with the Epstein-Barr virus-encoded associated nuclear antigen. J Clin Invest. 1986 May;77(5):1539–1547. doi: 10.1172/JCI112469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gaston J. S., Life P. F., Jenner P. J., Colston M. J., Bacon P. A. Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones. J Exp Med. 1990 Mar 1;171(3):831–841. doi: 10.1084/jem.171.3.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  13. Herzog C., Walker C., Pichler W., Aeschlimann A., Wassmer P., Stockinger H., Knapp W., Rieber P., Müller W. Monoclonal anti-CD4 in arthritis. Lancet. 1987 Dec 19;2(8573):1461–1462. doi: 10.1016/s0140-6736(87)91158-5. [DOI] [PubMed] [Google Scholar]
  14. Holoshitz J., Klajman A., Drucker I., Lapidot Z., Yaretzky A., Frenkel A., van Eden W., Cohen I. R. T lymphocytes of rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactive with cartilage. Lancet. 1986 Aug 9;2(8502):305–309. doi: 10.1016/s0140-6736(86)90003-6. [DOI] [PubMed] [Google Scholar]
  15. Koopman W. J. The future of biologics in the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 1994 Jun;23(6 Suppl 2):50–58. doi: 10.1016/0049-0172(94)90085-x. [DOI] [PubMed] [Google Scholar]
  16. Lacerda J. F., Ladanyi M., Louie D. C., Fernandez J. M., Papadopoulos E. B., O'Reilly R. J. Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce selective regressions of autologous EBV-induced B cell lymphoproliferations in xenografted C.B-17 scid/scid mice. J Exp Med. 1996 Mar 1;183(3):1215–1228. doi: 10.1084/jem.183.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Legrand L., Lathrop G. M., Marcelli-Barge A., Dryll A., Bardin T., Debeyre N., Poirier J. C., Schmid M., Ryckewaert A., Dausset J. HLA-DR genotype risks in seropositive rheumatoid arthritis. Am J Hum Genet. 1984 May;36(3):690–699. [PMC free article] [PubMed] [Google Scholar]
  18. Londei M., Savill C. M., Verhoef A., Brennan F., Leech Z. A., Duance V., Maini R. N., Feldmann M. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc Natl Acad Sci U S A. 1989 Jan;86(2):636–640. doi: 10.1073/pnas.86.2.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McMichael A. J., Sasazuki T., McDevitt H. O., Payne R. O. Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arthritis Rheum. 1977 Jun;20(5):1037–1042. doi: 10.1002/art.1780200501. [DOI] [PubMed] [Google Scholar]
  20. Newkirk M. M., Watanabe Duffy K. N., Leclerc J., Lambert N., Shiroky J. B. Detection of cytomegalovirus, Epstein-Barr virus and herpes virus-6 in patients with rheumatoid arthritis with or without Sjögren's syndrome. Br J Rheumatol. 1994 Apr;33(4):317–322. doi: 10.1093/rheumatology/33.4.317. [DOI] [PubMed] [Google Scholar]
  21. Res P. C., Schaar C. G., Breedveld F. C., van Eden W., van Embden J. D., Cohen I. R., de Vries R. R. Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet. 1988 Aug 27;2(8609):478–480. doi: 10.1016/s0140-6736(88)90123-7. [DOI] [PubMed] [Google Scholar]
  22. Rhodes G., Rumpold H., Kurki P., Patrick K. M., Carson D. A., Vaughan J. H. Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen. J Exp Med. 1987 Apr 1;165(4):1026–1040. doi: 10.1084/jem.165.4.1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Roudier J., Rhodes G., Petersen J., Vaughan J. H., Carson D. A. The Epstein-Barr virus glycoprotein gp110, a molecular link between HLA DR4, HLA DR1, and rheumatoid arthritis. Scand J Immunol. 1988 Apr;27(4):367–371. doi: 10.1111/j.1365-3083.1988.tb02359.x. [DOI] [PubMed] [Google Scholar]
  24. Ruggiero G., Racioppi L., Manzo C., Pirozzi G., D'Oro U., Ferrone S., Zappacosta S., Fontana S. HLA class II molecules on monocytes regulate T cell proliferation through physical interaction in the CD3 activation pathway. Eur J Immunol. 1991 Jan;21(1):29–33. doi: 10.1002/eji.1830210106. [DOI] [PubMed] [Google Scholar]
  25. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. doi: 10.1056/NEJM197804202981602. [DOI] [PubMed] [Google Scholar]
  27. Struyk L., Hawes G. E., Chatila M. K., Breedveld F. C., Kurnick J. T., van den Elsen P. J. T cell receptors in rheumatoid arthritis. Arthritis Rheum. 1995 May;38(5):577–589. doi: 10.1002/art.1780380502. [DOI] [PubMed] [Google Scholar]
  28. Tosato G., Steinberg A. D., Blaese R. M. Defective EBV-specific suppressor T-cell function in rheumatoid arthritis. N Engl J Med. 1981 Nov 19;305(21):1238–1243. doi: 10.1056/NEJM198111193052102. [DOI] [PubMed] [Google Scholar]
  29. Van Boxel J. A., Paget S. A. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. doi: 10.1056/NEJM197509112931101. [DOI] [PubMed] [Google Scholar]
  30. Venables P. Epstein-Barr virus infection and autoimmunity in rheumatoid arthritis. Ann Rheum Dis. 1988 Apr;47(4):265–269. doi: 10.1136/ard.47.4.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vie H., Chevalier S., Garand R., Moisan J. P., Praloran V., Devilder M. C., Moreau J. F., Soulillou J. P. Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder. Blood. 1989 Jul;74(1):285–290. [PubMed] [Google Scholar]
  32. Weyand C. M., Hicok K. C., Conn D. L., Goronzy J. J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992 Nov 15;117(10):801–806. doi: 10.7326/0003-4819-117-10-801. [DOI] [PubMed] [Google Scholar]
  33. Wong K. M., Levine A. J. Characterization of proteins encoded by the Epstein-Barr virus transactivator gene BMLF1. Virology. 1989 Jan;168(1):101–111. doi: 10.1016/0042-6822(89)90408-x. [DOI] [PubMed] [Google Scholar]
  34. Wong K. M., Levine A. J. Identification and mapping of Epstein-Barr virus early antigens and demonstration of a viral gene activator that functions in trans. J Virol. 1986 Oct;60(1):149–156. doi: 10.1128/jvi.60.1.149-156.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yocum D. E., Klippel J. H., Wilder R. L., Gerber N. L., Austin H. A., 3rd, Wahl S. M., Lesko L., Minor J. R., Preuss H. G., Yarboro C. Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. A randomized study. Ann Intern Med. 1988 Dec 1;109(11):863–869. doi: 10.7326/0003-4819-109-11-863. [DOI] [PubMed] [Google Scholar]
  36. Zhang L., Nikkari S., Skurnik M., Ziegler T., Luukkainen R., Möttönen T., Toivanen P. Detection of herpesviruses by polymerase chain reaction in lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1993 Aug;36(8):1080–1086. doi: 10.1002/art.1780360808. [DOI] [PubMed] [Google Scholar]
  37. Zoschke D., Segall M. Dw subtypes of DR4 in rheumatoid arthritis: evidence for a preferential association with Dw4. Hum Immunol. 1986 Jan;15(1):118–124. doi: 10.1016/0198-8859(86)90322-8. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES