Thyrotropin Receptor Blocking Antibodies

Abstract

Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves' disease and Hashimoto's thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance.

Fig. 1

Schematic of reporter gene-based functional bioassay for TBAb. CHO cells are engineered to constitutively express the human TSHR and to express luciferase following induction of cAMP. The binding of bovine (b) TSH to the TSH receptor on the surface of the cells induces a signaling cascade that leads to an increase of intracellular cAMP and subsequently to the luciferase expression. However, the presence of blocking anti-TSHR-Ab (TBAb) in serum of patients with autoimmune thyroid diseases inhibits the bTSH stimulation of the luciferase reporter gene. The TBAb level is correlated with blocking activity which is defined as percent inhibition of luciferase expression relative to induction with bTSH alone.

Fig. 2

Diagnostic flowchart for TSHR blocking antibody-induced hypothyroidism.