Mutational Analysis of Immunoglobulin Germline Derived Vλ4A Light Chains in Rheumatoid Arthritis

In order to better characterize the expression of a family of light chains previously expressed in IgM rheumatoid factors, we studied the usage and somatic mutational pattern of the Vλ4A light chain gene in rheumatoid arthritis (RA) patients. We sequenced 11 different transcripts of Vλ4A from the synovial tissue of three different RA patients. For comparison, we found 8 rearranged transcripts of Vλ4A from 4 normal peripheral blood lymphocyte libraries and 1 rearranged transcript from a non-RA con-A-resistant hybridoma in GenBank. A previously undescribed polymorphism of Vλ4A was noted. Furthermore, conserved replacement mutations in the complementary determining regions, common silent mutations around these replacement mutations, and two subsets of mutated sequences were detected in multiple RA patients. These mutation patterns also correlated with observed consistencies in the rearrangements of the Vλ4A/Jλ junction. These data suggest that there is clonal expansion of Vλ4A light chains in the RA synovium in response to a RA-specific antigen or as the result of an idiotypic response in RA.