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 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.
Yang
H
H
Department of Internal Medicine, Mayo Clinic Foundation, Rochester, MN, USA.
Rittner
H
H
Weyand
C M
CM
Goronzy
J J
JJ
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005787:Gene Frequency; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013585:Synovitis / Q000209:etiology / Q000235:genetics* / Q000276:immunology*
D017931:DNA Primers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D011948:Receptors, Antigen, T-Cell