T-CELL RECEPTOR OF FAS-SENSITIVE T-CELLS IN RHEUMATOID SYNOVIUM

Apoptosis is found in synoviocytes and CD3(+) T cells in the synovium of patients with rheumatoid arthritis (RA). To analyze the pathogenesi s of apoptosis in rheumatoid synovium, we examined the expression of F as Ag, Fas ligand (Fas-L), and TCR on T cells susceptible to anti-fas mAbs. Fas Ag is expressed on 40 to 60% of CD3(+) T cells in the synovi um as measured by immunohistochemical and flow cytometry methods. It w as observed by the reverse transcription-PCR method that Fas-L is over expressed on T cells infiltrating the rheumatoid synovium. These resul ts suggest that apoptosis in RA synovium is mediated by the Fas/Fas-L pathway. PCR-single-strand conformation polymorphism clearly demonstra ted that more than 50% of T cells that accumulate in synovium are remo ved by incubation with anti-fas mAbs for 24 h in vitro, indicating tha t these cells are Fas sensitive. Junctional sequence analysis revealed several conserved amino acids motifs (ERxxxSMNTE, IAAEGLLC, QxEGxD, V PD, TLAGxYNEQ, EPSE, STNxGEL, QGK, NIP, GLL, and KWT) in the CDR3 regi on of accumulated Fas-sensitive T cell clones, whereas these motifs we re not detected in Fas-resistant clones. In conclusion, our findings s upport the notion that Fas-sensitive T cells in rheumatoid synovium ar e generated by Ag stimulation and recognize relatively limited T cell epitopes on autoantigens, suggesting that susceptibility to anti-fas m Abs might be a selection marker for activated autoreactive T cells in RA.