STUDIES ON THE MOLECULAR BIOLOGY OF TSH RECEPTOR AND ON THE PATHOGENETIC ROLE OF ANTI-TSH RECEPTOR ANTIBODIES IN GRAVES' DISEASE

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Receptors on cell membranes generally play significant roles on the transduction of hormonal signals into cells, and abnormalities in hormone receptors closely relate to pathophysiology of several diseases. It is suggested that anti-TSH receptor antibodies play a causative role in Graves' disease, however, the molecular structure and functions of the TSH receptor have not been well clarified, making the pathogenetic significance of anti-TSH receptor antibodies still obscure. The aims of this study were as follows; 1) study on the molecular weight and the biochemical natures of the TSH receptor, 2) production of monoclonal antibodies to the TSH receptor and also of animal models of graves' disease, and 3) analysis of sequences of the cDNA of TSH receptor.We have shown that the TSH receptor is a glycoprotein, and that not only the stimulatory IgGs in patients with Graves' disease but also the blocking IgGs from patients with idiopathic myxedema react with the glycoprotein TSH receptor as well. After further purification using Graves' IgG-coupled sepharose, proteins were analyzed by Western blotting. The same 67KDa protein was stained by both the stimulatory and blocking type of IgGs suggesting that this antigen might relate to the TSH receptor.The preliminary results showed that some monoclonal antibodies against partially purified TSH receptor displaced the 125i-TSH binding to solubilized thyroid membranes stronger than others. Furthermore, we presented that the -interferon administered mice produced antithyroid antibodies in vivo, which advanced one step for making a new model of autoimmune thyroid diseases.The purpose no.3) remained undisolved in this study.