Elsevier

Autoimmunity Reviews

Volume 3, Issue 5, July 2004, Pages 362-367
Autoimmunity Reviews

Epstein–Barr virus and rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2004.02.002Get rights and content

Abstract

The cause of rheumatoid arthritis (RA) is still unknown. Both genetic and environmental factors may help its development. For 25 years, the Epstein–Barr Virus (EBV) has been suspected to contribute to RA pathogenesis. RA patients have higher levels of anti-EBV antibodies than healthy controls. EBV-specific suppressor T cell function is defective in RA. HLA-DRB1*0404, an RA predisposing allele, is associated with low frequencies of T cells specific for EBV gp110, a replicative phase glycoprotein critical for the control of EBV infection. Patients with RA have higher EBV load in peripheral blood lymphocytes (median 8.84 copies per 500 ng DNA) than healthy controls (median 0.6 copies/500 ng DNA). EBV, a widespread virus, highly recognized by antibodies but never eliminated, is an ideal candidate to trigger chronic immune complex disease. Anti-EBV antibody responses should be considered as one of the chronic autoantibody responses that are most relevant to the development of RA.

Section snippets

Genetic factors in RA

HLA-DRB1 alleles containing the QK/RRAA or RRRAA motif in their third hypervariable region (HVR3) carry susceptibility to develop RA [1]. Recently, Reviron et al. [2] have shown that HLA-DRB1 alleles can be classified into three groups: susceptible, like DR4 (except the DRB1*0402 and *0403 subtypes) and DR1, neutral, like DR3 and DR15, protective like DR7, DR8, DRB1*0402.

Epstein–Barr virus (EBV)

The Epstein–Barr virus (EBV or human herpesvirus 4) is a 172-kb double-stranded DNA virus. EBV is carried lifelong. It causes infectious mononucleosis and has been linked to the development of several malignant tumours including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and post transplant lymphoproliferative disease. In most people, primary infection and lifelong persistence are asymptomatic [3].

EBV first infects B lymphocytes or epithelial cells of the oropharynx. EBV

Rheumatoid arthritis and EBV

EBV infects almost the entire world adult population and for the past 25 years, a potential role of EBV in the pathogenesis of RA has been suspected.

First, Alspaugh et al. [5] reported that sera from RA patients contained high titers of antibody against a nuclear antigen present in EBV-infected cells. They later confirmed that sera from patients with RA contained high titer antibodies to latent and replicative EBV antigens like Epstein–Barr nuclear antigen (EBNA), viral capsid antigen (VCA),

Conclusions

Decreased T-cell response to gp110, an important EBV replication antigen, might lead to poor control of EBV infection and EBV overload especially in HLA-DRB1*0404 patients [11]. Generally, RA patients have high systemic EBV load and patients with active disease have low cellular response to gp110 [13], [23]. EBV is highly recognized by antibodies but is never eliminated. It is a perfect candidate to cause chronic immune complex disease. Anti-EBV antibody responses in RA patients are the

Take-home messages

  • RA patients have higher levels of anti-EBV antibodies than healthy controls.

  • EBV-specific suppressor T cell function is defective in RA.

  • Patients with RA have a 10-fold higher EBV load than healthy controls.

  • EBV is an ideal candidate to trigger chronic immune complex disease in RA.

Acknowledgements

This work was supported by grants from INSERM, Société Française de Rhumatologie (SFR), PHRC 2003.

References (23)

  • P.K Gregersen et al.

    The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

    Arthritis Rheum.

    (1987)
  • D Reviron et al.

    Influence of the shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis

    Arthritis Rheum.

    (2001)
  • P.G Murray et al.

    The Role of the Epstein–Barr virus in human disease

    Front Biosci.

    (2002)
  • P Murray et al.

    Epstein–Barr virus infection: basis of malignancy and potential for therapy

    Expert Rev. Mol. Med.

    (2001)
  • M.A Alspaugh et al.

    Differentiation and characterization of autoantibodies and their antigens in Sjogren's syndrome

    Arthritis Rheum.

    (1976)
  • M.A Alspaugh et al.

    Elevated levels of antibodies to Epstein–Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis

    J. Clin. Invest.

    (1981)
  • M Musiani et al.

    Comparison of the immune response to Epstein–Barr virus and cytomegalovirus in sera and synovial fluids of patients with rheumatoid arthritis

    Ann Rheum. Dis.

    (1987)
  • G Tosato et al.

    Defective EBV-specific suppressor T-cell function in rheumatoid arthritis

    N. Engl. J. Med.

    (1981)
  • G Tosato et al.

    Abnormally elevated frequency of Epstein–Barr virus-infected B cells in the blood of patients with rheumatoid arthritis

    J. Clin. Invest.

    (1984)
  • J Roudier et al.

    Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein–Barr virus glycoprotein gp110

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • E Toussirot et al.

    HLA-DR polymorphism influences T-cell precursor frequencies to Epstein–Barr virus (EBV) gp110: implications for the association of HLA-DR antigens with rheumatoid arthritis

    Tissue Antigens

    (1999)
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