Sera from patients with Grave's disease have been used to isolate autoantigens from a thyroid cDNA expression library. Thus far three clones for thyroid antigens have been isolated. One of these clones appears to be the receptor for thyroid stimulating hormone. Work on this clone is the areas of cDNA sequencing, gene structure, chromosomal location, tissue expression and in the development of assays for autoantibodies is in progress. Several potential autoantigen clones have recently been isolated from human pancreatic islet cell expression library using diabetic patients sera. Restriction fragment length polymorphism in the gene that encodes for thyroid stimulating hormone (TSH) receptor has been demonstrated in DNA samples obtained from normal individuals. This polymorphism is thought to be due to different alleles. Studies are underway with DNA from patients with thyroid diseases. Using fluorescence activated cell sorter B cells that are reactive with biotinylated self and non-self antigens (e.g., thyroglobulin, insulin, tetanus toxoid, etc.) were selected and immortalized by transformation with Epstein-Barr virus. Stable cell lines have been established by fusing these cells with a mouse-human heteromyeloma. Using limiting dilution analysis and EBV transformation of B lymphocytes cell lines capable of making human monoclonal antibodies to HIV and rabies virus have been established. Anti-idiotypic antibodies made against a panel of human monoclonal autoantibodies were used to quantitate autoantibody associated idiotopes in patients' sera with diabetes mellitus, Hashimoto's thyroiditis, systemic lupus erythematosus and normals. Our studies showed that these idiotopes are not only expressed on autoantibodies but also on immunoglobulins with unrelated specificities.