CLONAL V-ALPHA-12.1-CELL EXPANSIONS IN THE PERIPHERAL-BLOOD OF RHEUMATOID-ARTHRITIS PATIENTS( T)

Rheumatoid arthritis (RA) represents a heterogenous disease characteri zed by chronic polyarthritis. Most patients with adult RA inherit HLA- DR4 or -DR1 major histocompatibility complex (MHC) genes. While the mo lecular basis for this genetic predisposition is unknown, the major fu nction of these MHC-encoded molecules is to present peptides to T lymp hocytes. It is hypothesized that an endogenous or environmental antige n initiates a MHC-restricted immune response mediated by T lymphocytes , which is followed by a chronic inflammatory reaction involving many cell types. In chronic RA, previous or ongoing antigenic activation mi ght result in detectable skewing of the peripheral alpha/beta T cell r eceptor (TCR) repertoire. Here we demonstrate a marked expansion of Va lpha12.1-bearing CD8+ T cells in the peripheral blood (mean, 22%; rang e, 10-43%) of >15% of RA patients. A major proportion of these patient s shared HLA-DQ2 in addition to the expected high frequency DR1 and DR 4 alleles. Detailed molecular analysis in three of the RA patients wit h elevated Valpha12.1+ T cells identified repeated TCR alpha chain seq uences consistent with clonal Valpha12.1+,CD8+ T cell expansion. In ad dition to shared TCR Valpha12.1 germline gene usage among unrelated su bjects, a conserved Jalpha motif was also detected. Together, these re sults suggest an antigen-driven mechanism of T cell expansion in these patients and may offer a new approach in examining specific antigens that stimulate T cells in RA.