Aberrations in the primary T-cell receptor repertoire as a predisposition for synovial inflammation in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying th e HLA association and the generation of a synovial T-cell response are uncl ear. We have hypothesized that the selection of the primary T-cell repertoi re is a predisposing factor for rheumatoid synovitis, Methods: The repertoire of T-cell receptors (TCR) expressed by circulating naive CD4(+) CD45RO(-) T cells was compared in 10 patients with RA, 11 HLA- DR matched normal donors and 10 mismatched normal donors by determining the frequencies of TCR BV-BJ combinations in 3 different BV gene segment famil ies. Clonally expanded synovium-specific CD4 T cells were identified in 8 p atients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by si ze fractionation and sequencing of the PCR product, The TCR BV-BJ repertoir es of naive peripheral T cells and of synovial clones were compared, Results: The repertoires of naive circulating CD4+ CD45RO(-) T cells were d ifferent in RA patients and in HLA-DR matched and unmatched controls, sugge sting HLA-DR as well as disease-specific features of T-cell selection. To t est the disease relevance of the shifts in the naive repertoire, CD4 T cell s undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and si gnificantly different from the expected distribution with a preference for combinations favored in the naive TCR repertoire of,RA patients. Conclusions: These data suggest that primary T-cell selection in RA patient s is of functional importance for the generation of synovium-specific T-cel l responses, The synovial repertoire is influenced by aberrations in the na ive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.