Epstein–Barr virus and rheumatoid arthritis Nathalie Balandraud, Jean Roudier * , Chantal Roudier INSERM U639, Faculte ´ de Me ´decine, Marseilles 13005, France Ho ˆpital de La Conception, Service de Rhumatologie, APHM, Marseille 13005, France Received 12 February 2004; accepted 25 February 2004 Available online 9 April 2004 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. D 2004 Elsevier B.V. All rights reserved. Keywords: Rheumatoid arthritis; Epstein – Barr virus Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with a 0.5% world- wide prevalence. RA leads to the destruction of synovial joints and to systemic manifestations. Its cause is unknown. Both genetic and environmental factors are supposed to contribute to RA susceptibil- ity. Among environmental factors, numerous infec- tious agents have been suspected: Epstein–Barr virus is the most interesting. We try here to summarize the links between EBV and RA. 1. 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. 1568-9972/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2004.02.002 * Corresponding author. Ho ˆpital de la Conception, Service de Rhumatologie, 147 Bd Baille, Marseille 13005, France. Tel.: +33- 491-32-44-97; fax: +33-491-83-09-26. E-mail address: jean.roudier@medecine.univ-mrs.fr (J. Roudier). www.elsevier.com/locate/autrev 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. D 2004 Elsevier B.V. All rights reserved. Keywords: Rheumatoid arthritis; Epstein – Barr virus Autoimmunity Reviews 3 (2004) 362 – 367