A functional site on the human TSH receptor: a potential therapeutic target in Graves' disease.
OBJECTIVE
Identifying sites on the TSH-receptor that are involved in the pathological stimulation of the thyroid by autoantibodies in Graves' disease would aid the development of new therapies. We tested a series of monoclonal antibodies that recognize the native receptor for their ability to inhibit stimulation of the receptor in vitro.


METHODS
Heterologous cells expressing the recombinant human TSH-receptor were stimulated with TSH or serum samples from 13 Graves' disease patients or the MRC Long-Acting Thyroid Stimulator standard B (LATS-B) and their cAMP responses measured. The effect on this stimulation of various doses of purified monoclonal antibodies with defined epitopes was determined.


RESULTS
Antibodies against one epitope (residues 381-384) inhibited TSH-stimulated cyclic adenosine monophosphate (cAMP) production (1 microg/ml causing 50% inhibition of the response to 100 microU/ml TSH) and also inhibited cAMP production induced by sera from approximately 40% (6/14) of Graves' disease patients, including the MRC LATS-B standard.


CONCLUSIONS
Residues 381-384 of the human TSH-receptor are important in the physiological and pathological stimulation of the thyroid. This opens the possibility of more specific therapy of some Graves' disease patients by agents directed against this epitope.
D000818:Animals; D000911:Antibodies, Monoclonal; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006111:Graves Disease / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D051379:Mice; D011989:Receptors, Thyrotropin / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D011989:Receptors, Thyrotropin; D000242:Cyclic AMP