Thyroid Research Thyroid Research Archive Graves' Disease

Separation of the receptor for thyrotropin from thyroid cells may be important in Graves' hyperthyroidism

(November 2002)

The background of the study. The cause of hyperthyroidism in patients with Graves' disease is stimulation of thyroid hormone production by antibodies (thyrotropin [TSH] receptor-stimulating antibodies [TSHR-SAb]) that bind to and activate receptors for TSH, just as does TSH. The receptors are long molecules that extend from outside thyroid cells through their outer membrane to the inside (cytoplasm) of the cells. TSHR-SAb and TSH bind primarily to the end of the receptor that lies outside the cells, and much of this end can be cleaved from the remainder and released into the extracellular fluid that surrounds the cells. This study was done to determine the reactivity of different parts of the receptor with TSH and TSHR-SAb.

How the study was done. Intact TSH receptors or the end segment of the receptor anchored to the cell membrane were expressed in hamster ovary cells. The cells were incubated with serum samples from 20 patients with Graves' hyperthyroidism that contained TSHR-SAb, from 7 patients with hypothyroidism that contained TSH receptor-blocking antibodies (TSH-BAb), and from 9 normal subjects who had neither type of antibody. The cells were then stained to determine if any TSHR-SAb was bound to them.

The results of the study. Serum from 17 of the 20 patients with Graves' hyperthyroidism bound to the cells containing the end segment of the TSH receptor better than to the cells containing intact receptors. In contrast, serum from patients with hypothyroidism bound equally well to both types of cell. Serum from normal subjects did not bind to either type of cell. Preincubation of cleaved end segments with serum from patients with Graves' hyperthyroidism abolished serum binding to the cells.

The conclusions of the study. TSHR-SAb in serum from patients with Graves' hyperthyroidism bind preferentially to the end-and most exposed-segment of the TSH receptor, and the binding is blocked by preincubation with cleaved end segments. The natural release of end segments into extracellular fluid may be an important source of antigen for production of TSHR-SAb.

The original article. Chazenbalk GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM, Rapoport B. Thyroid-stimulating autoantibodies in Graves' disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. J Clin Invest 2002;110:209-17.