Autoantibodies to the Thyrotropin Receptor

Abstract

This review considers recent developments in our understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis. Two new assay methods have allowed considerable improvements in the sensitivity, specificity, precision, and ease of measuring TRAb. In particular: 1) receptor assays based on inhibition of receptor-purified labeled TSH binding to detergent-solubilized TSH receptors and 2) bioassays based on stimulation of cAMP release from monolayer cultures of isolated thyroid cells. Detailed studies with the two assays indicate that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism. Studies in areas of dietary iodine sufficiency suggest that measurement of the antibodies at various stages in the course of treating Graves' disease can be of value in predicting the outcome of therapy. However, in areas of iodine deficiency, difficulties in the ability of patients' thyroid tissue to recover from the effects of antithyroid drugs may prevent the receptor antibodies from causing a relapse of thyrotoxicosis. Consequently, the predictive value of receptor antibody measurements would be expected to be lower in these geographical areas. Although patients with a history of Graves' hyperthyroidism nearly always have TRAb which act as TSH agonists, about 20% of patients with frank hypothyroidism due to autoimmune destruction of the thyroid have TRAb which act as TSH antagonists (blocking antibodies). There is some evidence that these blocking antibodies can cause hypothyroidism particularly in the neonate. With regard to the site of synthesis of TRAb, there is now direct evidence that they are synthesized by thyroid lymphocytes, particularly the lymphocytes in close proximity to thyroid follicular cells. This is consistent with the well established effects of antithyroid treatment (drugs, radioiodine, or surgery) on TRAb levels in addition to their effects on thyroid hormone synthesis. Recent studies using affinity labeling with 125I-labeled TSH have enabled elucidation of the structure of the TSH receptor. TSH receptors in human, porcine, and guinea pig thyroid tissue have a two-chain structure in which the TSH binding site is formed on the outside surface of the cell membrane by a water-soluble A subunit (Mr approximately 50 K). The A subunit is linked by a disulfide bridge and weak noncovalent bonds to the amphiphilic B subunit (Mr approximately 30 K). This subunit, which penetrates the lipid bilayer, probably forms the site for interaction of the receptor with the regulatory subunits of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

Engineering the Human Thyrotropin Receptor Ectodomain from a Non-secreted Form to a Secreted, Highly Immunoreactive Glycoprotein That Neutralizes Autoantibodies in Graves' Patients' Sera

“…1 Thus autoantibodies to the TSHR activate the receptor, leading to thyroid overactivity and thyrotoxicosis (reviewed in Ref. 2). The interaction between autoantibodies and the TSHR is, therefore, of interest from the theoretical, diagnostic, and (potentially) therapeutic points of view.…”

Association study of autoimmune thyroid disease at 5q23-q33 in Japanese patients

“…GD patients without and with ophthalmopathy were 111 and 88, respectively. For anti-TSH receptor antibodies, TBII (TSH binding inhibitor immunoglobulin) activity (Rees Smith et al 1988;Endo et al 1978) was measured, because TBII activity was most frequently measured at the onset of GD as an anti-TSH receptor antibody. GD patients with potent ( ‡50%) and weak (<50%) TBII were 64 and 90, respectively.…”

Thyroid Stimulating Immunoglobulin(TSI) in Graves' Disease.

“…When TBII (with TSH receptor assay) and TSAb [CAMP production in porcine thyroid cells (PTC) assay] were determined, all LATS positive sera showed extremely high TSAb and TBII activities [12]. All available data indicate that TSH and TSAb may bind to the same site on the TSH receptor and that TSAb may be TRAb with a thyroid stimulating action [1,2]. Abnormally negative values in the TRAb (TBII) assay led to the discovery of bTSH binding antibody.…”

“…TSAb and TSBAb are determined by measuring CAMP (marker of thyroid stimulation) produced in thyroid cells exposed to IgG in the absence and presence of TSH, respectively [1,2]. Since clarification of the structure of the TSH receptor the binding epitope for TRAb has been studied, but the nature of the epitope for TRAb is still controversial.…”