Inhibition of Functional and Immunological Responses to Thyroid-Stimulating Antibodies from Patients with Graves' Disease by Blockade of the Thyrotropin Receptor

Abstract

Thyrotropin (TSH) receptor is the main autoantigen and the target of thyroid-stimulating antibodies in Graves' disease. In the present studies, in order to shed further light on the role of TSH receptor in thyroid autoimmune disease, we investigated the effects of TSH receptor blockade on functional and immunological responses to thyroid stimulation by Graves' immunoglobulins in the nude mouse bearing human thyroid transplants. Injecting the nude mice with purified Graves' immunoglobulins G resulted in a dose-dependent stimulation of thyroid hormone production, an inducement of cellular hypertrophy of transplant thyrocytes, and an expression of the HLA-DR antigen by up to 75% of the transplant thyroid follicular cells. Treatment of the animals with the TSH receptor antagonist asialoagalacto-hCG was able to inhibit the stimulation by Graves' immunoglobulins G of thyroxine production, cellular hypertrophy of transplant thyrocytes, and HLA-DR expression by thyroid follicular cells in the human transplants. The present data provide direct evidence for an involvement of the human TSH receptor in mediating both the functional disturbance (hyperthyroidism) and the immunological disorder in Graves' disease and add further support to the concept of using TSH receptor antagonists in the management of the disease.

Inhibitory Effect of Thyroid Blocking Antibody (TBAb) on the Thyroid Stimulatory Effect of Human Chorionic Gonadotropin (HCG ) and Equine Chorionic Gonadotropin (ECG)

“…deglycosylated-HCG (asialo-or asialoagalacto-HCG) is a competitive antagonist of TSH binding to TSHR. Because of increased TSHR binding compared to HCG, it has blocking action on cAMP production by TSH and TSAb [6][7][8][9][10][11]. in the present experiment we examined the inhibitory effect of TBAb on the thyroid stimulating activity of HCG and ECG.…”

“…There are many reports that HCG has the thyroid hormone releasing activity via TSHR binding [3][4][5][6][7][8][9][10][11]. Furthermore, the thyroid stimulating activity of HCG is blocked by TBAb [11].…”

“…deglycosylated HCG (asialo-or asialoagalacto-HCG) is a competitive antagonist of TSH because of increased TSHR binding compared to HCG. An inhibitory effect of asialo-HCG or asialoagalacto-HCG on the thyroid stimulating activity of TSAb has been reported [6][7][8][9][10]. These facts suggest that TSH, TSAb, HCG and deglycosylated-HCG may bind to a similar region of TSH R. in the present study we examined the effects of TBAb on the thyroid stimulating activity of HCG and equine chorionic gonadotropin (ECG).…”

“…Inhibitory Effect of Thyroid Blocking Antibody (TBAb) on the Thyroid Stimulatory Effect of Human Chorionic Gonadotropin (HCG) and Equine Chorionic Gonadotropin (ECG) YukiO OCHi 1) , MASAnARi HAMAZu 2) , YOSHiHiRO kAJiTA 3) , TAkASHi HACHiYA 4) And MASARu HAMAOki 5) roid stimulating activity through binding to the TSHR [3][4][5][6][7][8][9][10][11]. deglycosylated HCG (asialo-or asialoagalacto-HCG) is a competitive antagonist of TSH because of increased TSHR binding compared to HCG.…”

Metabolism of glucose and glutamine in lymphocytes from graves' hyperthyroid patients: influence of methimazole treatment

“…The treatment of Graves' hyperthyroidism with methimazole (MMI),' mainly in combination with thyroid hormones,233 restores the immunological control of the disea~e.4~~ A decrease in certain circulating thyroid autoantibodies against thyroid peroxidase (TPOab), thyroglobulin (TgAb) and the TSH-receptor (TRAb) has been observed.2i3p6 The importance of the immune effect of MMI is also indicated by the fact that there is a higher remission-rate of Graves' hyperthyroidism with MMI treatment213 as compared with spontaneous resolution or treatment with pr~panolol.~ These immune effects could be obtained throu h a and in the restoration of the suppressor T-cell reduction in the thyroid antigen signalling 5 function once euthyroidism is reached." In fact and intrathyr~id'~ lymphocytes that include thyroid autoantibodies can be inhibited by MMI.…”