Figure 1.

Inferring the role of EBV in RA synovitis. EBV is present in RA synovium, and LMP-1 expressed in synovial lining cells may suppress SAP function [56,104] and breaks down the normal defense mechanism against infection with EBV [85,103]. EBV activation might contribute to synovial cell proliferation, inflammation, and autoantibody production [52], and may be involved in the induction of RA synovitis. Additionally, environmental factors may contribute to EBV reactivation as follows: (1) Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to production of citrullinated peptides both in the gingiva and synovium [105]. (2) This bacterium also produces butyric acid, which induces EBV reactivation [106]. (3) Enhanced lytic replication of EBV induced by dioxin and tobacco is also a risk factor for the development of autoimmune diseases [107,108]. EBV infection in humanized NOG mice resulted in a pathological condition characterized by erosive arthritis that is also seen in human rheumatoid arthritis; EBV infection is thus thought to be directly involved in RA pathogenesis [92].