BACKGROUND: Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying the HLA association and the generation of a synovial T-cell response are unclear. We have hypothesized that the selection of the primary T-cell repertoire 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 families. Clonally expanded synovium-specific CD4 T cells were identified in 8 patients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by size fractionation and sequencing of the PCR product. The TCR BV-BJ repertoires of naive peripheral T cells and of synovial clones were compared. RESULTS: The repertoires of naive circulating CD4+ CD45RO- T cells were different in RA patients and in HLA-DR matched and unmatched controls, suggesting HLA-DR as well as disease-specific features of T-cell selection. To test the disease relevance of the shifts in the naive repertoire, CD4 T cells undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and significantly 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 patients is of functional importance for the generation of synovium-specific T-cell responses. The synovial repertoire is influenced by aberrations in the naive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.
BACKGROUND:Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying the HLA association and the generation of a synovial T-cell response are unclear. We have hypothesized that the selection of the primary T-cell repertoire 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 families. Clonally expanded synovium-specific CD4 T cells were identified in 8 patients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by size fractionation and sequencing of the PCR product. The TCR BV-BJ repertoires of naive peripheral T cells and of synovial clones were compared. RESULTS: The repertoires of naive circulating CD4+ CD45RO- T cells were different in RApatients and in HLA-DR matched and unmatched controls, suggesting HLA-DR as well as disease-specific features of T-cell selection. To test the disease relevance of the shifts in the naive repertoire, CD4 T cells undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and significantly different from the expected distribution with a preference for combinations favored in the naive TCR repertoire of RApatients. CONCLUSIONS: These data suggest that primary T-cell selection in RApatients is of functional importance for the generation of synovium-specific T-cell responses. The synovial repertoire is influenced by aberrations in the naive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.
Authors: Sun Jung Kim; Sebastian Schätzle; S Sohail Ahmed; Wolfgang Haap; Su Hwa Jang; Peter K Gregersen; George Georgiou; Betty Diamond Journal: Nat Immunol Date: 2017-07-10 Impact factor: 25.606