A MINOR GROUP OF RHEUMATOID FACTORS ISOLATED FROM A PATIENT WITH RHEUMATOID-ARTHRITIS IS DERIVED FROM SOMATICALLY MUTATED VK1-GENES FURTHER EVIDENCE THAT RHEUMATOID FACTORS DURING AUTOIMMUNE-DISEASES UNDERGO AN ANTIGEN-DRIVEN MATURATION

To better understand the structural basis for rheumatoid factor [RF] activity and the origin of autoantibodies in human autoimmune diseases, we isolated the RF producing B cells from the peripheral blood and from the synovial fluid of a patient suffering from rheumatoid arthritis [RA]. We previously demonstrated that a significant fraction of these RF were derived from three V(kappa)III genes known to encode most of the monoclonal RF light chain variable regions. To get more insight into the actual repertoire of RF-V(kappa) genes during RA, we analyzed the nucleotide sequences of RF light chain variable regions of other V(kappa) families. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from RF producing cells from the same patient KRA, we isolated only three different rearranged V(kappa)-J(kappa) complexes: slkv5, slkv7 and bkv42, all derived from V(kappa)I germ-line genes not previously known to be associated with RF activity; this suggests that the repertoire of VL genes coding for RF during RA is more diverse than the one involved in the generation of paraprotein RF during monoclonal lymphoid proliferations, although there remains a possible bias in favor of the V(kappa)III family. Moreover, each of these genes is somatically mutated with a pattern suggesting a selective pressure of the antigen. Particularly interesting is the additional proline residue at the V(kappa)-J(kappa) junction of bkv42, an unorthodox feature that we found previously in more than 50% of RF V(kappa)III-J(kappa) gene complexes. Finally, the homogeneity of some non conservative mutations suggests the existence of a restricted set of pathogenic epitopes driving the production of RF during RA.