Bernard Rees Smith

RELATION OF THYROID-STIMULATING IMMUNOGLOBULINS TO THYROID FUNCTION AND EFFECTS OF SURGERY, RADIOIODINE, AND ANTITHYROID DRUGS

Thyroid-stimulating immunoglobulins (T.S.I.) have been detected in the serum of all patients with untreated Graves disease, and in these patients the levels of T.S.I. correlated significantly with the early uptake of 131I by the thyroid. The frequency of T.S.I. in patients treated solely by antithyroid drugs, by radioiodine, or by partial thyroidectomy was 53 per cent, 50 per cent, and 17 per cent, respectively. The reduced frequency of T.S.I. in the serum of patients treated by drugs or radioiodine was probably due to spontaneous remission, but in the case of partial thyroidectomy the operation itself clearly had a dramatic effect on the serum-T.S;I. These results accorded well with the reported frequency of thyroid autonomy in similar groups of patients and suggested that thyroid-stimulating immunoglobulins were responsible for hyperthyroidism in Graves disease.

Binding of thyroid stimulators to thyroid membranes

Thyroid-stimulating hormone (TSH) and the thyroid-stimulating immunoglobulin described as long acting thyroid-stimulator (LATS) have been shown to bind to receptors in the thyroid [ 1 6 ] . However, reports on the interaction of immunoglobulins with LATS activity on the binding of labelled TSH to its receptor appear to be conflicting. Fayet et al. [5] have reported that LATS serum incompletely inhibited the binding of labelled TSH to intact thyroid cells whereas Amir et al. [6] were unable to demonstrate any action of LATS on TSH binding to isolated thyroid membranes. This paper describes the effects of immunoglobulins from several LATS sera on the binding of labelled TSH to thyroid membranes.

THE INTERACTION OF THYROID-STIMULATING ANTIBODIES WITH SOLUBILISED HUMAN THYROTROPHIN RECEPTORS

Thyroid receptors for thyrotrophin (TSH) and thyroid-stimulating antibodies (TSAb) are closely related as indicated by the ability of TSAb to inhibit the binding of labelled TSH to thyroid membranes [l-4] and to isolated thyroid cells [S ,6] . The effect of TSAb on the TSH-TSH receptor interaction may be due to direct binding of the antibody to the TSH receptor. Alternatively, TSAb may bind to a site different from the TSH receptor in such a way as to induce changes in the thyroid membrane and cause inactivation of the TSH receptor. In order to investigate these two possibilities we have studied the interaction between TSAb and solubilised human TSH receptors. Our data indicate that TSAb inhibits the binding of labelled TSH to soluble TSH receptors and provide evidence for the concept that TSAb is an antibody to the TSH receptor.

Kinetics of immunoglobulin production by cultured human peripheral blood lymphocytes

A study of immunoglobulin synthesis by human peripheral blood lymphocytes cultured in Marbrook flasks is described. Maximal amounts of immunoglobulin were produced by 3 weeks and most of this was synthesised between 6 and 21 days. In the region of 90% of the immunoglobulin was secreted into the medium. Pokeweed mitogen (PWM) stimulated cultures produced about 10 times as much immunoglobulin as cells cultured in medium only. After 21 days stimulated cultures produced about 150 microgram of IgG, 125 microgram of IgM and 50 microgram of IgA per 10(7) cells.

THYROTROPHIN RECEPTOR BINDING, INTRACELLULAR CYCLIC AMP LEVELS AND IODINE RELEASE IN ISOLATED THYROID CELLS

There is now considerable evidence that hormonereceptor interactions activate adenylate cyclase and the resulting increases in cyclic AMP levels mediate the effects of the hormone [ 1 ] . However, a study of corticotrophin (ACTH) stimulation of cyclic AMP production and steroidogenesis in isolated adrenal cells has suggested that cyclic AMP is not involved in the stimulation of steroidogenesis by small amounts of ACTH [2]. Similarly, human chorionic gonadotrophin (hCG)-stimulated testosterone production in dispersed interstitial cells appears to be independent of changes in cyclic AMP levels [3]. Scranton and Tong [4] have reported that thyrotrophin (TSH) causes a rapid stimulation of iodine release from isolated thyroid cells in the absence of stimulation of iodine uptake and in this paper. We describe a study of the relationship between TSH stimulation of iodine release, intracellular cyclic AMP levels and TSH receptor binding using isolated porcine thyroid cells. Since sera from patients with Graves’ disease contain antibody molecules which mimic the effects of TSH by interacting with the TSH receptor [S] , the effects of these Graves’ immunoglobulins on the isolated thyroid cells have also been studied.

Membrane receptors for polypeptide hormones.

Publisher Summary The chapter reviews the study of the binding of radioactively labeled hormones to various target cell membranes. The first stage in the mechanism of action of the large peptide hormones, which include growth hormone (GH), luteinizing hormone (LH), chorionic gonadotropin (CG), follicle-stimulating hormone (FSH), thyroidstimulating hormone (TSH), prolactin (PRL), corticotropin (ACTH), insulin, glucagon, and parathyroid hormone (PTH) is the contact with hormone- specific receptor sites on the target cell surface. The hormone receptor interaction appears to modify the cell in such a way to activate the membrane-bound enzyme adenyl cyclase and possibly guanyl cyclase. This increased enzyme activity leads to increased intracellular levels of cyclic nucleotides, which mediate the actions of the hormone. The mechanism by which the hormone-receptor interaction activates adenyl cyclase is completely unknown at present, but the relationship between receptor binding and cyclic nucleotide production is studied in several tissues. The chapter also reviews the recent work that indicates that antibodies to hormone receptors play a major role in the pathogenesis of some diseases.

Thyroglobulin Autoantibody IgG Subclasses; Regulation By T Cells

Microsomal and thyroglobulin (Tg) antibodies in patients with autoimmune thyroid disease are usually restricted to subclasses IgGl and/or IgG4 (1,2) and this distribution is likely to reflect the capacity of these antibodies to induce thyroid damage (3).