Differential use of immunoglobulin light chain genes and B lymphocyte expansion at sites of disease in rheumatoid arthritis (RA) compared with circulating B lymphocytes.

The presence of germinal centre-like structures and clonotypic expansion of lymphocytes in RA synovia may indicate a site-specific immune response to local antigens, rather than passively entrapped immune cells, that sustains synovial inflammation. In this study we compare the nature of immunoglobulin light chain variable region gene use in the synovium of RA patients with peripheral B cells to determine the nature of the synovial immune response. Using Vlambda and Vkappa gene fingerprinting, which relies on differences in CDR3 length, we demonstrate differences in the pattern of Vlambda and Vkappa use and clonotypic expansion of B cells between the synovium and peripheral blood of RA patients. Further, we show that some synovial rearrangements with long CDR3 are selectively expanded. These longer than usual CDR3 were generated by a number of mechanisms including N-additions. However, the observed differences were not uniform in different patients. These observations suggest that local synovial antigens drive significant numbers of T and B lymphocytes selected from an existing repertoire shaped by genetic and environmental factors. Further, the data argue against passive retention of most B cells in the synovium of RA patients.