Thyrotropin receptor autoantibodies in thyroid autoimmune disease: Epitopes and origin

Abstract

The present report outlines developments since the recent cloning of the TSHR that have allowed definition of epitopes for TSHRAbs present in some autoimmune thyroid diseases and important in the expression of the disease. These studies have indicated that the major TSHR autoantibody determinants are TSHR-specific; this accounts for their specific association with autoimmune thyroid disease and their inability to perturb gonadal function. Since there are different epitopes for stimulating and blocking TSHRAbs, this accounts for the different types of thyroid autoimmune disease associated with receptor autoantibodies, for example, hyperthyroidism and Graves' or hypothyroidism and idiopathic myxedema, respectively. In the course of studies examining receptor regulation at a gene level, a link to the development of these and other thyroid autoantibodies seems to be emerging. This involves regulation of MHC class I genes and their modulation by negative regulatory factors normally expressed in the presence of the multiplicity of hormones important for normal, regulated thyroid function, including TSH. Subversion of negative regulation is suggested to result in autoimmune disease. The result of the loss of negative regulation (Fig. 3) would increase expression of all thyroid specific autoantigens: TSHR, thyroglobulin, and thyroid peroxidase. There would also be an increase in MHC class I gene expression and aberrant class II expression since the negative regulatory factors for each may be interlocked. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal.