PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

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Research will be conducted in an effort to establish basic abnormalities in the function of the immune system leading to thyroid autoimmunity and the clinical disease syndromes of Graves' disease, thyroiditis, and idiopathic myxedema. Thyroid microsomal antigen will be solubilized, purified by immunoabsorption or immunoprecipitation, separated by electrophoresis, and identified by Western Blotting. Cell surface and membrane proteins will be iodinated or labeled with 35S methionine. Proteins will be separated by electrophoresis and antigens will be detected by Western Blot. Preliminary studies have shown that different sera recognize different antigen epitopes in non-denaturing, denaturing, or reduced and denaturing conditions. We will relate the type of antibody reaction pattern to the clinical features of the disease. Preliminary data has suggested that the microsomal antigen is closely related to thyroid peroxidase, and a variety of studies will be pursued in order to prove or disprove this possibility. We will detect different epitopes on the microsomal antigen using cyanogen bromide or protease V8 fragmentation of the antigen and Western blotting or column techniques. An attempt will be made to identify the specific antigens to which patients with AITD most frequently are immunized. In order to study function of the feedback control system regulating microsomal antibody production, we will look for microsomal antigen in serum, and will develop methods for recognizing anti-idiotype antibodies directed against microsomal antibody epitopes. T cell reactivity to microsomal antigen will be characterized using lymphocytes from peripheral blood, thyroid tissue, or neck lymph nodes. T cell clones will be developed using a soft agar culture or test tube incubation system. The T cell lines will be used in studies of control of B cell function and in vitro reactivity with autologous thyroid cells. If sufficient time is available, we will attempt to clone the gene for the microsomal antigen and assess differences in structure or expression of the gene.