Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody
Year: 2004
Type: article
Abstract: Thyrotropin receptor (TSHR) Ab's of the stimulating variety are the cause of hyperthyroid Graves disease.MS-1 is a hamster mAb with TSHR-stimulating activity.To examine the in vivo biological activity of MS-1, mice were treated with purified MS-1 intraperitoneally and the thyroid response evaluated.MS-1 induced a dose-dependent increase in serum thyroxine (T4), with a maximum effect after 10 μg of MS-1 was administered.MS-1-secreting hybridoma cells were then transferred into the peritoneum of nude mice to study chronic thyroid stimulation.Serum MS-1 levels detected after 2 weeks were approximately 10-50 μg/ml, and the serum TSH was suppressed in all animals.Serum triiodothyronine levels were elevated, but only in animals with low serum MS-1 concentrations.In addition, there was a negative correlation between serum T4 and the serum MS-1 concentrations.These in vivo studies suggested a partial TSHR inactivation induced by excessive stimulation by MS-1.We confirmed this inactivation by demonstrating MS-1 modulation of TSHR function in vitro as evidenced by downregulation and desensitization of the TSHR at concentrations of MS-1 achieved in the in vivo studies.Thus, inactivation of the TSHR by stimulating TSHR autoantibodies (TSHR-Ab's) in Graves disease patients may provide a functional explanation for the poor correlation between thyroid function and serum TSHR-Ab concentrations.Nonstandard abbreviations used: CHO cell lines stably expressing the human thyrotropin receptor (CHO-hTSHR); CHO cell lines stably expressing the mouse thyrotropin receptor (CHO-mTSHR); thyrotropin (TSH); thyrotropin receptor (TSHR); thyrotropin receptor autoantibody (TSHR-Ab); thyroxine (T4); triiodothyronine (T3). Conflict of interest:The authors have declared that no conflict of interest exists.
DOI: 10.1172/jci200421334
Authors: Takao Ando, Rauf Latif, Terry F. Davies
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2067298006