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Submitted on June 7, 2004
Accepted on August 10, 2004
I.R.I.B.H.M., Faculté de Médecine, University of Brussels, 808 Lennik street, B-1070, Brussels, Belgium (S.C., J.V.D., G.V.); Institute of Endocrine Sciences, University of Milan, Istituto Auxologico Italiano IRCCS and Ospedale Maggiore di Milano IRCCS, Italy (M.B.); Research Department, B.R.A.H.M.S AG, Biotechnology Center Hennigsdorf, Berlin, Germany (N.G.M.); Biochemie-Zentrum-Heidelberg, University of Heidelberg, Im Neuenheimerfeld 328, 69120 Heidelberg, Germany (V.P.); Department of Medicine and Pediatrics, University of Chicago, Chicago Ill.60637 (S.R.); Department of Genetics, Erasme Hospital, University of Brussels, Belgium (G.V.)
* To whom correspondence should be addressed. E-mail: gvassart{at}ulb.ac.be.
An experimental murine model of Graves' disease was used to produce monoclonal antibodies (mAbs) with thyroid stimulating activity (TSAb). Two of these, IRI-SAb2 and IRI-SAb3, showed particularly high potency (in the low nanomolar range) and efficacy. IRI-SAb2 behaved as a full agonist of the human TSHr, even when tested in physiological salt concentrations. Both IRI-SAb2 and IRI-SAb3 were displaced from the TSHr by autoantibodies from patients with Graves' disease or harboring thyroid blocking antibodies, but not from control subjects or patients with Hashimoto thyroiditis. The epitopes of IRI-SAb2 and IRI-SAb3 were precisely mapped, at the aminoacid level, to the aminoterminal portion of the concave portion of the horseshoe structure of TSHr ectodomain. They overlap closely with each other and, surprisingly, with the epitope of a mAb with blocking activity. When injected iv in mice, both mAbs caused biological and histological signs of hyperthyroidism. Unexpectedly, they triggered also an inflammatory response in the thyroid glands. Delineation of the conformational epitopes of these stimulating antibodies, opens the way to the identification of the molecular mechanisms implicated in the activation of the TSHr.
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