Synovial T cell receptor heterogeneity in early arthritis

Rheumatoid arthritis (RA) has been postulated to result from a synovial immune response to an unidentified antigen(s), which should be mirrored by the T cell response. Here we investigate the T cell receptor (TCR) repertoire in the synovial tissue of patients with arthritis of early to moderate duration. We developed a nested polymerase chain reaction (PCR) technique to examine the TCR repertoire of small biopsy specimens, and show that the method is highly sensitive. We apply this technique to synovial biopsies obtained from the knee joints of patients with early to moderate duration arthritis (average duration of arthritis 1 year, range 0. 02-2.75 years). We examined biopsies from 5 normal individuals, 32 RA patients, 7 patients with seronegative spondyloarthropathy (Sp), and 12 patients with undifferentiated arthritis (UA). TCR message was detectable in 4/5 normals, 15/32 RA, 5/7 Sp, and 8/11 UA biopsies, with sampling error likely accounting for most negative biopsies. The average numbers of TCR Vbetas detected per TCR-positive biopsy were 5.0 +/- 3.7 for normals, 12.7 +/- 8.4 for RA, 18.0 +/- 7.4 for Sp patients, and 14.4 +/- 10.2 for UA. Examination of TCR messages by single-stranded conformational polymorphism analysis showed similar proportions of dominant clones in the normals compared with the patients with inflammatory arthritis. Sequence analysis was performed on 33 dominant clones from 16 patients. Sequence alignment of the third hypervariable regions showed some evidence of disease-specific sequence clustering for Sp, while some RA sequences showed similarity to previously described motifs. These data indicate greater TCR heterogeneity in early Sp and UA compared with normal synovium. Disease-specific TCR sequences may occur in early RA and Sp.