Mutational Analysis of Immunoglobulin Germline Derived V lambda 4B Light Chains in Rheumatoid Arthritis

We investigated the somatic mutational pattern of a specific V lambda light chain variable region (V) gene in rheumatoid arthritis (RA) patients. The V lambda 4B light chain was chosen because of its location on the lambda locus and because of its previously observed use in IgM rheumatoid factors. Methods: We sequenced 13 different mRNA transcripts of V lambda 4B from the synovium of three different RA patients. These were compared to 31 identifiable V lambda 4B sequences from GenBank, which were obtained from the PBL of patients without RA. Results: A subset of V lambda 4B had a high rate of mutation, especially in the framework regions within the RA synovium. Furthermore, a set of codons within the first complementary determining region of V lambda 4B displayed frequent replacement mutations but did not possess any silent mutations. The hypermutation of RA synovial-derived V lambda 4B sequences, especially in the framework areas, may contribute to or may be the result of altered mutational mechanisms and/or prolonged B cell life.