Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis.

Abstract

Clonal expansion of T cell specificities in the synovial fluid of patients has been taken as evidence for a local stimulation of T cells. By studying the T cell receptor (TCR) repertoire of CD4± T cells in the synovial and peripheral blood compartments of patients with early rheumatoid arthritis (RA), we have identified clonally expanded CD4 + populations. Expanded clonotypes were present in the peripheral blood and the synovial fluid but were not preferentially accumulated in the joint. Dominant single clonotypes could not be isolated from CD4+ cells of HLA-DRB1 *04+ normal individuals. Clonal expansion involved several distinct clonotypes with a preference for Vf633, V1314', and VJ817'CD4+ T cells. A fraction of clonally related T cells expressed IL-2 receptors, indicating recent activation. The frequencies of clonally expanded V/317+CD4+ T cells fluctuated widely over a period of one year. Independent variations in the frequencies of two distinct clonotypes in the same patient indicated that different mechanisms, and not stimulation by a single arthritogenic antigen, were involved in clonal proliferation. These data support the concept that RA patients have a grossly imbalanced TCR repertoire. Clonal expansion may result from intrinsic defects in T cell generation and regulation.The dominance of expanded clonotypes in the periphery emphasizes the systemic nature of RA and suggests that T cell proliferation occurs outside of the joint. (J. Clin. Invest. 1994. 94

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

“…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). These clonal expansions involved only a limited number of clonotypes, and were smaller and less widespread than the clonal expansion we have observed after CAMPATH-1H treatment.…”

“…Complementary DNA from CD4+ T cells derived from peripheral blood before and after treatment and derived from synovial tissue after treatment were amplified by PCR with the appropriate Vp-specific primer set (Vp5.l or Vp8, depending on the clonal specificity). The amplified template was dot-blotted onto supported nitrocellulose membranes, immobilized, and prehybridized as described (26). The membranes were then hybridized with a biotinylated Cp probe (ACACAGCGAC-CTCGGGTGGGGA) and probes specific for the junctional polymorphisms of the VpS.…”

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…Second, this skewing is a primary event, rather than merely a consequence of inflamma- tion, since the unaffected siblings of RA patients also display expanded T cell clonotypes (46,47). Third, although alterations have been noted in the peripheral compartment (48), they are more pronounced in the joint, are similar in different joints in the same patient, and are stable over time (49,50). Finally, the ability to transfer disease to SCID mice by injection of RA synovial T lymphocytes suggests a pathogenic role for these cells (51).…”

HLA-DRB1*0402 (DW10) Transgene Protects Collagen- Induced Arthritis-Susceptible H2Aq and DRB1*0401 (DW4) Transgenic Mice from Arthritis

“…This might explain stronger in vitro response to CII immunization and development of arthritis in DW4 mice and not in DW10 mice. Recent studies have shown oligoclonal expansion of T cells in periphery and joints of RA patients, which is thought to be driven in part by CII, suggesting that T cells reactive to CII may be mediators of RA pathogenesis (50,51). In double transgenic mice resistant allele is able to modulate the development of arthritis by lower amounts of inflammatory cytokines and increased apoptosis leading to decreased incidence.…”