Persistence of dominant T cell clones in synovial tissues during rheumatoid arthritis.

Abstract

In a previous study, we showed that the T cell repertoire is biased in the synovial membrane (SM) compared with peripheral blood during rheumatoid arthritis (RA). The same bias was observed in different joints from the same patient and seems to be the same over time. To discover whether this bias was due to expansion of a clonal subset resulting from activation by conventional Ag(s) or to polygonal stimulation by superantigen(s), we sequenced more than 650 TCRBV-D-J junctional regions from freshly isolated SM and peripheral blood of two DR4-RA patients. From each patient, two SM were obtained on the same day, and a third was obtained later. Several dominant clones were found in SM but not in peripheral blood. Some of them were found only at the first time point in anatomically different SM, the majority persisted over time, and others were detected only at the second time point. Analysis of the complementarity-determining region 3 (CDR3) showed a bias in TCRBD and amino acid usage. Valine, encoded by randomly inserted N nucleotides, was used by 45% of dominant clones compared with 18% in the control population (p less than 0.001). In addition, GXXG and TSG motifs were frequently observed in the CDR3 of these dominant clones. These data indicate a dynamic TCR selection process during the perpetuation phase of RA. The dynamic changes of dominant clones also suggest a determinant spreading mechanism during RA.

The Search for the Pathogenic T Cells in the Joint of Rheumatoid Arthritis: Which T-Cell Subset Drives Autoimmune Inflammation?

“…Although RA has long been regarded as a T-cell-mediated autoimmune disease, it is still challenging to demonstrate autoreactivity of T cells in RA joints. Based on the assumption that pathogenic, autoreactive T cells likely expand in the joints of RA patients, the clonality of synovial T cells has been studied by examining TCRVβ usage [ 60 , 61 , 62 ] or analyzing the complementarity-determining region 3 (CDR3) sequence [ 63 ]. Yamamoto et al developed a method to comprehensively evaluate TCR clonality, single-strand conformation polymorphism (SSCP) analysis, while others performed spectratyping of CDR3 length, both of which showed T-cell clonal expansion [ 64 , 65 ].…”