Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients.
Rheumatoid arthritis (RA) represents a heterogenous disease characterized by chronic polyarthritis. Most patients with adult RA inherit HLA-DR4 or -DR1 major histocompatibility complex (MHC) genes. While the molecular basis for this genetic predisposition is unknown, the major function of these MHC-encoded molecules is to present peptides to T lymphocytes. It is hypothesized that an endogenous or environmental antigen 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 might result in detectable skewing of the peripheral alpha/beta T cell receptor (TCR) repertoire. Here we demonstrate a marked expansion of V alpha 12.1-bearing CD8+ T cells in the peripheral blood (mean, 22%; range, 10-43%) of > 15% of RA patients. A major proportion of these patients shared HLA-DQ2 in addition to the expected high frequency DR1 and DR4 alleles. Detailed molecular analysis in three of the RA patients with elevated V alpha 12.1+ T cells identified repeated TCR alpha chain sequences consistent with clonal V alpha 12.1+,CD8+ T cell expansion. In addition to shared TCR V alpha 12.1 germline gene usage among unrelated subjects, a conserved J alpha motif was also detected. Together, these results suggest an antigen-driven mechanism of T cell expansion in these patients and may offer a new approach in examining specific antigen that stimulate T cells in RA.
Department of Rheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
H
H
DerSimonian
M
M
Sugita
D N
DN
Glass
A L
AL
Maier
M E
ME
Weinblatt
T
T
Rème
M B
MB
Brenner
D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001483:Base Sequence; D016827:CD8 Antigens / Q000032:analysis; D006683:HLA-DQ Antigens / Q000032:analysis; D006801:Humans; D007156:Immunologic Memory; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis*; D013583:Synovial Membrane / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D016827:CD8 Antigens; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D009838:Oligodeoxyribonucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta