Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients.

Abstract

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.

Emergence of oligoclonal t cell populations following therapeutic t cell depletion in rheumatoid arthritis

“…Clonal abnormalities of circulating T cells have been described in RA patients. Clonal expansions have been found predominantly in CD8+ T cells studies have shown that clonal expansion can be found in at least 10% of the RA population studied (34). We have also observed clonal expansion of CD4+ T cells in patients with RA (26).…”

Cd8high+ (CD57+) T cells in patients with rheumatoid arthritis

“…In addition to the TCR V, MAb, we also studied TCR V,12 expression (data not shown) and did not observe an increased frequency of TCR V,12+ expansions (2 of 25 RA patients versus 2 of 24 controls) as previously reported (37). There are a number of possible explanations that may account for the differences between our and other (34-37) studies.…”

“…Second, different antigens may generate the CD8high+(CD57+) subset. Third, TCR usage may be biased by HLA haplotypes; for example, an association between increased frequency of TCR V,12 and HLA-DQw2 has been described (37). We found no significant associations between RA patients with TCR V,5 and V,13 expansions and their MHC I haplotypes, though the small numbers and the nature of the anti-TCR V,5 and V,13 MAb (discussed above) preclude any conclusions concerning MHC restriction.…”

Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis

“…Of note, DerSimonian et a1 recently found that -15% of RA patients without neutropenia or lymphocytosis demonstrated clonal expansions of CD8+ T cells bearing the VJ2.1 T cell receptor (15). However, among those 8 patients, only 3 were DR4+, although 7 of the 8 were DQ2+ (15). No such increase in DQ2 was seen in our patients with LGL leukemia plus RA.…”

“…This pattern is not consistent with proliferation of LGL due to a superantigen, which should induce a restricted pattern of T cell receptor V, usage. Of note, DerSimonian et a1 recently found that -15% of RA patients without neutropenia or lymphocytosis demonstrated clonal expansions of CD8+ T cells bearing the VJ2.1 T cell receptor (15). However, among those 8 patients, only 3 were DR4+, although 7 of the 8 were DQ2+ (15).…”