Analysis of the molecular basis of synovial rheumatoid factors in rheumatoid arthritis

The objective of this study was to better understand the molecular basis of IgM rheumatoid factor in rheumatoid arthritis (RA). We recently generated 10 different monoclonal IgM RF (mRF) molecules isolated from the synovium of a single patient with RA. The heavy (H) and light chain (L) variable region (V) genes of these 10 mRFs were cloned and sequenced. Six mRFs used kappa light chains and 4 mRFs used lambda light chains. Of particular interest, 8 of 10 heavy chains used the JH4 joining region gene, and all five VH4 heavy chains used the DK4 diversity region gene with the JH4. Four of the VH4 clones used the same germline gene, likely representing a novel but closely related germline gene to VH4.18, and may be clonally related because of the extensive homology in their heavy chain sequence. Two VH4 clones shared the same light chain gene, VkappaIIIb kv325 (99% homology) and the same JK4 joining region gene, while three VH4 clones used two different light chain genes, an uncommon Vkappa4 and a Vlambda4 gene, respectively. In this RA patient, there was recurrent utilization of VH4-DK4-21/10-JH4 genes and a recurring association with gene elements Vkappa3 and Vlambda4. Recurring usage of Vkappa3 (kv325) and Vlambda4 (lv418) gene elements may result from a light chain editing process whereby immature autoreactive B cells encountering self-antigen attempt, and often succeed, in altering their specificities through secondary Ig light chain gene rearrangement. Moreover, the oligoclonality of these RFs suggest clonal relatedness secondary to an antigen-driven response.