Evidence that human immunoglobulin m rheumatoid factors can be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts

The question of whether immunoglobulin (Ig)M rheumatoid factors (RF) arise as the result of an abnormal expansion of already existing clones producing natural autoantibodies or emerge as new clones that are somatically mutate d owing to an antigen driven immune response has never been conclusively an swered. In this study, an inhibition ELISA was utilized to measure the affi nities of recombinant antibodies using V-H segments reverted back to their closest germline counterparts (germline revertants). In all cases, the soma tically mutated parental RFs had a decreased affinity for immunoglobulin (I g)G Fc compared to the germline revertant, indicating that the antibodies i n the germline configuration had the higher affinities. This demonstrates t hat somatic mutation is not a prerequisite to generate disease associated a ntibodies. The presence of mutations in the parental IgM RFS suggests that these cells had been involved in a germinal centre reaction. As the germina l centre is the conventional site of the acquisition of mutations during an antigen driven response, these data suggest a role for germinal centres in the generation of the antibody diversity in addition to the selection of h igher affinity antibodies. Assuming that only antigen selected cells surviv e deletion, these data support the hypothesis that IgM RFS can be derived f rom the natural autoantibody repertoire and result from an antigen driven r esponse. Mechanisms controlling the survival of B cells based on the affini ty/avidity of the immunoglobulin receptor are shown to be functional in pat ients with rheumatoid arthritis.