The pathogenesis of rheumatoid arthritis (RA) remains unclear. However, accumulated studies indicate that RA is a multifactorial disease, influenced by both genetic and environmental factors. For example, DR4, Dw4 and Dw14 as well as certain polymorphic markers in Ig gene loci have been associated with RA. Interestingly, the linkage between DR4 and RA is significant mainly in RA patients with rheumatoid factors (RF), which have been implicated in the production of chronic tissue damage in the inflamed joints. Recently, our preliminary data suggest that disease relevant synovial IgG RFs are monoclonal in one RA patient and are bi-clonal in another RA patient, analogous to the finding of monoclonal and oligoclonal IgG RFs in individual autoimmune mice. These observations imply the occurrence of one or a few dominant clones of IgG RF B cells due to antigen selection. In addition to IgG RFs, T cells from rheumatoid synovia were found to respond vigorously to mycobacterial antigens, which induce arthritis in rats; the majority of such T cells were gammadelta T cells. Combined, these findings suggest gammadelta T cells may play a major role in joint destruction. Thus, to examine the hypothesis that RA is a multifactorial disease, affected by both genetic and environmental factors, we intend to analyze globally the disease-relevant IgG RFs and the synovial T cell receptor (TCR) Vgamma gene in early RA patients and well characterized RA twins of different HLA haplotypes, and to decipher the underlying genetic and environmental factors which influence the expression of such RFs and TCR Vgamma gene. Specifically, we will: I) develop methodologies for rapid analyses of the expressed H chain V (Vh) genes that encode IgG RFs in RA patients; II) analyze IgG RF Vh genes in 10 pairs of monozygotic twins who are concordant for RA, and 10 pairs of monozygotic twins who are discordant for RA; III) determine the genotypes of the selected Ig V genes in all analyzed individuals; IV) characterize the expressed TCR Vgamma genes in the inflamed joints and blood of early RA patients; V) compare the disease-relevant TCR Vgamma genes in the 20 aforementioned monozygotic twins; VI) determine the genotypes of the reported polymorphic TCR Vgamma genes in all analyzed individuals. Together, these studies will reveal the effects of RA-related genetic factors on the expression of the disease related Ig V genes and TCR Vgamma genes, and such information may advance our understanding of the pathogenesis of RA.

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