PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

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Autoimmune thyroid disease (Graves' disease, thyroiditis, myxedema) affects 6% of women during their life span. The cause is probably multifactorial involving abnormal presentation of antigen, aberrant DR expression, and abnormalities in T cell suppressor circuits. We hypothesize that T cell immunization to thyroid microsomal antigen is a major factor in autoimmune thyroid disease, and we will analyze carefully the interaction of T cells and microsomal antigen. Antigen specific T cell clones derived from thyroid tissue would be investigated for their ability to control B cell specific antibody production, cytotoxicity directed to thyroid cells, and induction of immunoregulatory responses. A dominant epitope will be sought in microsomal antigen-thyroid preoxidase by defining immunoreactivity of T cell clones to purified microsomal antigen, peptide fragments, and synthetic peptides. The T cell receptor variable V alpha and V beta segments will be cloned and sequenced to determine whether one V segment is favored in gene rearrangement forming T cell receptors. An idiotypic monoclonal antibody directed to the T cell receptor of microsomal antigen specific T cell clones will be developed. Release of microsomal antigen-thyroid peroxidase from thyroid cells cultured in vitro will be analyzed, in an effort to determine how the immune system is exposed to the antigen. The studies should define the epitope(s) on thyroid microsomal antigen recognized by T cells, and the specific responses of the T cells to the antigen. If there is a dominant microsomal antigen epitope, or limited epitopes, monoclonal antibodies to the T cell receptor for the antigen could allow development of specific immunosuppressive therapy. Our analysis of the V alpha and B beta gene segments may define the use of favored segments in T cell receptor gene rearrangement, and thus identify a hereditable factor which could be important in the development of these diseases.