Abstract
ObjectiveThe objective of the present study was to investigate Epstein-Barr virus (EBV) infection as an environmental factor for the development of rheumatoid arthritis (RA).MethodsSynovial tissues were collected during surgery from 128 RA and 98 osteoarthritis (OA) patients. DNA was extracted from synovial tissues. The EBV gene was assessed by nested PCR for the amplification of EBV nuclear antigen-1 (EBNA-1). The nucleotide sequence of the PCR product was elucidated. HLA-DRB1 genotyping was also performed.ResultsEBV DNA was more frequently detected in the synovial tissues of RA patients (32.8%) than OA patients (15.3%) (p<0.01). The frequency of EBNA-1 variants did not significantly differ between RA and OA (RA: 17%, OA: 13%). The population with the HLA-DRB1 shared epitope (SE) was significantly higher in RA patients (70.3%) than in OA patients (44.9%) (p<0.001). In RA patients, the presence of EBV DNA was similar among SE-positive and -negative patients (SE-positive: 34.4%, -negative: 28.9%). The population with the EBNA-1 variant did not significantly differ between SE-positive and -negative patients (SE-positive: 12.9%, -negative: 27.3%).DiscussionThe present results indicate that EBV infection contributes to the onset of RA and chronic inflammation in synovial tissues. The frequency of EBNA-1 gene variants was low and not significantly different between RA and OA, suggesting that EBNA-1 gene variants are not a risk factor for RA. HLA-DRB1 with SE is a genetic risk factor for the development of RA. However, neither the presence of EBV nor EBNA-1 gene variants differed between SE-positive and -negative RA patients. Therefore, these two risk factors, SE and EBV, may be independent.ConclusionEBV infection may be an environmental risk factor for the development of RA, while nucleotide variants of EBNA-1 do not appear to contribute to its development.
Highlights
Rheumatoid arthritis (RA) is characterized by chronic inflammation in multiple joints
Epstein-Barr virus (EBV) DNA was more frequently detected in the synovial tissues of RA patients (32.8%) than OA patients (15.3%) (p
In RA patients, the presence of EBV DNA was similar among shared epitopes (SE)-positive and -negative patients (SE-positive: 34.4%, -negative: 28.9%)
Summary
Rheumatoid arthritis (RA) is characterized by chronic inflammation in multiple joints. Human leukocyte antigen DRB1 (HLA-DRB1) alleles have been shown to influence susceptibility to and the severity of RA. The first indication to a relationship between EBV and RA was reported in 1978, showing that antibodies against EBV nuclear antigen (EBNA) differ between RA patients and normal controls [4]. Several studies have shown that latent membrane protein-1 (LMP1) as well as EBNA-2 and Epstein–Barr virus-encoded small RNAs (EBER) could be detected in the synovial tissue in patients with RA [8,9,10,11,12,13]. Takei et al showed that mRNA expression of EBV-specific cytotoxic T-cell-associated molecule signaling lymphocytic-activation molecule-associated protein (SAP) was decreased in the peripheral leukocytes or T cells, which may lead to failure of the immune system to eliminate EBV in RA patients [14]. A large proportion of anti-citrullinated protein/peptides antibodyproducing plasma cells surrounding synovial germinal centers were infected with EBV [16]
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