CONSERVED MOTIFS IN RHEUMATOID-ARTHRITIS SYNOVIAL TISSUE T-CELL RECEPTOR BETA-CHAINS

Rheumatoid arthritis is genetically linked to major histocompatibility complex (MHC) molecules (HLA-DR4 and related molecules) and character ized pathologically by high levels of HLA-DR expression and infiltrati on of proliferative of synovial tissue with CD4+ T lymphocytes. T-lymp hocyte activation is driven by specific signaling through polymorphic alpha/beta T-cell receptors (TCRs) that are reactive with antigen-MHC complexes present at the sites of inflammation. We are interested in c haracterizing rheumatoid TCRs molecularly to ascertain potential bindi ng surfaces for antigen + MHC in synovial tissue. Accordingly, we have recently investigated the TCR alpha and beta chain heterogeneity in a series of 10 rheumatoid synovia obtained at the time of joint surgery . The most frequently detected Vbeta families were Vbeta12, 14, and 17 , each of which was found in 80% of specimens. We report here the mole cular cloning and sequence analysis of 20 cloned Vbeta segments amplif ied with a Vbeta14 family-specific TCR primer, and six cloned Vbeta se gments amplified with a Vbeta17 family-specific TCR primer from four r heumatoid synovia. Comparison with the data base revealed that these s equences belonged to the closely related Vbeta3, Vbeta14, and Vbeta17 families. Dominant clones were apparent in two of the individuals by t he presence of identical V-D-J regions, suggesting an antigen-driven p rocess. Amino acid sequence analysis revealed a conserved motif in the putative fourth hypervariable region or CDR4. Molecular modeling of t his epitope suggests that charged side chains are available for bindin g to ligand structures (e.g., antigen, MHC, or superantigen). We sugge st this epitope may play a role in the molecular pathogenesis of rheum atoid arthritis.