The synovium in seropositive rheumatoid arthritis (RA) is capable of producing marked amounts of immunoglobulin. Up to 5-10% of the synovial antibody repertoire has rheumatoid factor (RF) activity, which is thought to be intimately involved in disease pathogenesis. However, the three idiotypes most commonly expressed by IgM RF paraproteins (Wa, Po and Bla) appear to be a minor component of synovial RF. Thus, the genetic composition of the RA synovial antibody repertoire, both non-RF and RF, is unknown. This proposal outlines analysis of the antibody repertoire expressed in rheumatoid synovium to test the hypothesis that synovial immunoglobulin production is antigen-driven and, thus, involved in disease pathogenesis. Data from murine models validate this approach. Sequence analyses of antibody repertoires in MRL/lpr mice suggest that autoantibodies generated during nonspecific stimulation by LPS are polyclonal and reflect the germline repertoire; whereas in autoimmune states, self-reactive antibodies are clonally related and characteristic of antigen-driven production. Murine models also suggest that the physico-chemical properties of specific V germline elements influence the manifestations of autoimmune disease. Thus, polymorphism in the genomic repertoire may be an additional, independent factor in disease susceptibility. The antibody repertoires of cDNA libraries made from rheumatoid synovial cells will be characterized at the nucleotide sequence level, seeking evidence of restriction in V region utilization in Cmu- and Ckappa-containing transcripts. Sequences will be compared to germline and pathologic gene segments. Evidence of oligoclonal expansion will be sought by analyzing the VH-DH-JH joins of Cgamma- and Calpha-containing transcripts and the Vkappa-Jkappa joins. The extent of somatic mutation will provide further evidence regarding possible antigen-driven selection. Combinatorial libraries will be generated to assess antigen specificity. Candidate germline autoreactive elements will be identified, the extent of polymorphism in the human population analyzed, and possible correlation to disease susceptibility established. These studies should help elucidate a poorly understood manifestation of rheumatic disease and serve as reference for future studies of abnormal immune responses. The proposed training plan involves two years of graduate courses and initial laboratory experience (Phase I). When advisory committee criteria for advancement are met, the candidate will have three years of intensive research experience (Phase II).
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