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,§
*
Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206;
NeXstar Pharmaceuticals, Inc., Boulder, CO 80301; and Departments of
Medicine and
§
Immunology, University of Colorado Health Sciences Center, Denver, CO 80262
The role of T cells in the pathogenesis of rheumatoid arthritis
(RA), especially in the perpetuation of advanced disease, remains
unclear. Previous studies have focused on the TCR repertoire of
synovial T cells in an attempt to determine whether the pattern of
expression is characteristic of Ag-stimulated populations. However, the
results of past studies have been conflicting. In the present work, we
have undertaken an extensive analysis of the TCRs expressed by
CD4+ T cells freshly isolated from synovial fluid of
different joints and blood in three patients with established RA.
Despite marked heterogeneity of synovial TCR expression, the results
showed that 20 to 30% of the TCR ß-chain gene (TCRB)
sequences found in one joint were also expressed in a second joint, but
not in peripheral blood T cells of the same individual. Analysis of
expressed TCRB complementarity-determining region 3
sequences showed the presence of multiple expanded clonal populations
that were not predicted by quantitation of ß-chain variable region
(Vß) expression by immunofluorescence staining. These studies also
demonstrated sets of related, but different,
complementarity-determining region 3 nucleotide sequences that encoded
identical or highly homologous ß-chain amino acid sequences. Analysis
of matching T cell clones derived from the joint by limiting dilution
culture confirmed coexpression of highly homologous TCR 
-chain gene
(TCRA) and TCRB sequences. Together,
these studies suggest that a significant proportion of synovial
CD4+ T cells has been selected and expanded by conventional
Ag(s) in this disease.
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