ReviewEpstein-Barr virus and rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with a 0.5–1% worldwide prevalence [1]. RA leads to synovial joint destruction and to systemic manifestations but its pathophysiology remains unclear [2].
Both genetic (HLA-DRB1 polymorphism [3]) and environmental factors contribute to RA susceptibility. HLA-DRB1 genes code for HLA-DR molecules expressed at the surface of antigen-presenting cells. HLA-DR molecules present peptides and may help autoantibody production. Seventy percent of RA patients express HLA–DR molecules containing the QKRAA/QRRAA or RRRAA motif (the shared epitope) in their third hypervariable region (HVR3) [4]. Shared epitope motifs carry disease susceptibility. Among the environmental factors, numerous infectious agents have been suspected: Epstein-Barr virus (EBV) is the most interesting. Its possible implication was first shown by Alspaugh and Billings who demonstrated that sera from most patients with RA contained antibodies against Epstein-Barr virus nuclear antigen (EBNA-1), initially called rheumatoid arthritis nuclear antigen (RANA) [5].
Both RA patients and solid organ transplant recipients are at increased risk of developing lymphoma [6]. In solid organ transplant recipients under immunosuppressants, emergence of lymphoma can be predicted by monitoring the EBV load in peripheral blood mononuclear cells (PBMCs) [7].
Here, we review the association between EBV and RA, from the aetiopathogenesis of RA to the development of EBV+ lymphoma in patients with RA.
Section snippets
EBV [8]
EBV (or human herpesvirus 4) is a widely disseminated lymphotropic herpes virus implicated in benign and malignant disorders. It was first discovered in Burkitt lymphoma in 1964. EBV infects B lymphocytes and epithelial cells and its biology follows that of a normal mature B lymphocyte. It can persist for a lifetime in a non-pathogenic state in resting memory B cells [9].
EBV is a 172-kb linear double-stranded DNA virus. Primary infection, most often asymptomatic, occurs in 90% of young
Molecular mimicry between EBV and self proteins
RA susceptibility is carried by HLA-DRB1* alleles containing the QK/RRAA or RRRAA motif in their third hypervariable region. This motif is known as the shared epitope [12].
There are several examples of molecular similarities between EBV and self-antigens relevant to RA. The QKRAA amino acid sequence of HLA-DRB1*04:01 can also be found in the EBV glycoprotein gp110 [13]. EBV gp110, encoded by the BALF4 open reading frame, is a major replicative antigen, involved in infection control. It is
Conclusion
EBV is a common etiologic factor for SLE, RA, and Sjögren's syndrome, all diseases associated with high titres of anti-EBV antibodies, a high proportion of EBV-infected B cells, a high EBV load in peripheral blood and an increased risk of lymphoma.
The relationship between EBV and autoimmune diseases is complex and involves different mechanisms. Molecular mimicry between EBV proteins and self-antigens provides a possible model for disease induction. Genetic predisposition and T cell dysfunction
Disclosure of interest
The authors declare that they have no competing interest.
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