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Heterogeneity of the Graves' Immunoglobulins Directed toward the Thyrotropin Receptor-Adenylate Cyclase System^*

Pierre Carayon, Grazyna Adler, Roger Roulier and Serge Lissitzky

Laboratoire de Biochimie Medicate, U38INSERM, Faculte de Medecine, Marseilte, France

Address requests for reprints to: Dr. P. Carayon, Laboratoire de Biochimie Medicale, Faculte de Medecine, 27, Boulevard Jean Moulin, F-13385 Marseille Cedex 5, France.

The TSH-displacing and the thyroid-stimulating activities of Graves' immunoglobulins G (GIgG) have been accounted for by either homogeneous TSH receptor antibodies or heterogeneous antibodies directed toward the TSH receptoradenylate cyclase system. To clarify this matter, the study of the interactions of GIgG preparations from 14 untreated Graves' patients with human thyroid membranes was undertaken. Dose-response curves of GIgG, diluted in IgG from normal subjects, were carried out in the [¹²⁵I]TSH radioreceptor assay and the adenylate cyclase assay in the presence or absence of TSH. In the radioreceptor assay, GIgG were constantly negative in 3 cases (21%) and positive, depending of the dose, in 11 cases. In the adenylate cyclase assay, the dose-activity profiles in the absence of TSH were bell-shaped curves in 3 cases and sigmoid curves in 9 cases; in 2 cases (14%), GIgG preparations were devoid of any effect. Binding-isotherms and dose-activity profiles did not appear to share simple relationships. In the presence of TSH, GIgG preparations elicited a decrease in 6 cases, an increase in 3 cases, and no effect in 5 cases (36%) in the adenylate cyclase activity. The data obtained by radioreceptor assay and adenylate cyclase assay in the presence or absence of TSH were found statistically correlated (P < 0.05 to P < 0.001) but not linearly related, the points being scattered on specific parts of the diagrams. These observations could not be accounted for by TSH receptor antibodies in GIgG being an entity of constant properties, albeit varying in titer among patients. Rather, GIgG effects fit well the patterns of action of a heterogeneous ligand, as shown by computing a theoretical model for ligand heterogeneity with respect to binding equilibrium constant and intrinsic biological activity. Accordingly, GIgG activity in the TSH receptor-adenylate cyclase system could be attributed to heterogeneous antibodies varying with regard to binding constant and acting as stimulating or blocking antibodies of the adenylate cyclase. (J Clin Endocrinol Metab 56:1202,1983)

^* Presented in part at the XI Annual Meeting of the European Thyroid Association, September 1981, Pisa, Italy.

Research Fellow of the Ministere des Relations Exterieures, France; present address: Medical Center of Postgraduate Education, Warszawa, Marymoncka 99, Poland.

Received August 1, 1982.

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