Autoantibodies to the TSH Receptor—from discovery to understanding the mechanisms of action and to new therapeutics

Abstract

Prior to 1956, Graves’ hyperthyroidism was thought to be due to high levels of TSH but in that year Adams & Purves demonstrated the presence of a thyroid stimulator in Graves’ sera with a prolonged time course of action (long-acting thyroid stimulator, LATS) quite distinct from TSH. LATS was only present in the serum IgG fraction suggesting it was a thyroid stimulating autoantibody. In 1974 Graves’ IgG was shown to compete with ¹²⁵I-labelled TSH for the TSH receptor providing good evidence that Graves’ hyperthyroidism was caused by TSH receptor autoantibodies. Further breakthroughs occurred in 1989 (TSHR cloning) and 2003 (monoclonal thyroid stimulating autoantibody M22^TM). Subsequently atomic level detail of how TSHR stimulating (2007) and blocking (2011) autoantibodies interact with the TSHR became available. Cryo-EM studies followed (2022–2025) and provide a detailed understanding of how TSHR autoantibodies with different properties function. The human monoclonal autoantibody K1-70^TM with powerful TSH receptor blocking activity is now in clinical trials. It has the expected beneficial effects on Graves’ hyperthyroidism and Graves’ ophthalmopathy and is an exciting new TSHR specific drug.