Autoantibodies are present in rheumatic diseases as well as certain neoplastic and lymphoproliferative disorders, but factors responsible for their production remain unclear. Recent advances suggest that autoantibodies may be expressed as part of the preimmune repertoire. Monoclonal IgM paraproteins with rheumatoid factor (RF) activity have been shown to preferentially use germline encoded light chains of the kappa III subgroup. However, the relative contribution of different immunoglobulin variable region genes to autoantibody diversity in patients with autoimmune disease has been difficult to study. To address this problem, we propose to use peptide-induced antisera with defined specificity for each human heavy and light chain variable (V) region subgroup and to determine if the polyclonal RF populations from patients with different autoimmune diseases preferentially use certain inherited V region gene elements. In initial experiments, we shall compare: 1) RF from patients with rheumatoid arthritis and Sjogren's syndrome; 2) RF isolated from synovial fluid and sera; 3) RF of different isotypes; 4) RF isolated at different times from the same patient. Heavy and light chain subgroup analysis may also be applied to other autoantibodies. Later, after completion of coursework in cellular immunology and molecular biology, tools will be developed to better characterize the inheritance and expression of V genes, in various patient populations. If a predominant subgroup is expressed in an expanding pathologic autoantibody population, it may be possible to use subgroup specific peptides in the development of active immunotherapy.
