Practical applications of studies on the TSH receptor and TSH receptor autoantibodies

J Furmaniak,J Sanders,P Sanders,M M Ryder,B Rees Smith,J Miller-Gallacher

doi:10.1007/s12020-019-02180-9

Abstract

Studies on the TSH receptor (TSHR) have numerous practical applications in vitro and in vivo. For example human monoclonal autoantibodies (MAbs) to the TSHR are useful reagents for in vitro diagnostics. Measurement of TSHR autoantibodies (TRAbs) is helpful in diagnosis and management of autoimmune thyroid disease. Currently available highly sensitive and specific assays to measure TRAbs use the human TSHR MAb M22 instead of the TSH. Furthermore, preparations of the human TSHR MAb M22 are useful as the World Health Organisation International Standard for thyroid stimulating antibody and for calibration of the assays for measuring TRAbs. Preparations of thermostabilised TSHR extracellular domain have recently become available and this is likely to have an impact on improvements in specificity testing for TRAb assays. In addition the stable TSHR preparations have practical application for specific immunoadsorption of patient serum TRAbs. Human TSHR MAbs also have promising prospects as new therapeutics. Autoantibodies with TSHR antagonistic activities are “natural” inhibitors of TSHR stimulation and are expected to be helpful in controlling TSHR activity in patients with Graves’ disease, Graves’ ophthalmopathy and thyroid cancer.

Highlights

The presence in patient sera of the long-acting thyroid stimulator (LATS), distinct from TSH, was first described in 1956 by Adams and Purves [1]
This key observation resulted in development of the first in vitro receptor binding assay to measure TSH receptor (TSHR) autoantibodies (TRAb) to help in the diagnosis and management of autoimmune thyroid disease (AITD)
Advances in recombinant TSHR gene expression combined with the availability of human monoclonal autoantibodies (hMAbs) culminated in crystallising the complexes of the TSHR leucine rich repeat domain (LRD) with M22 Fab and with K1-70 Fab [10, 11]

Summary

Introduction

The presence in patient sera of the long-acting thyroid stimulator (LATS), distinct from TSH, was first described in 1956 by Adams and Purves [1]. Almost two decades later in 1974, pivotal studies by Smith and Hall showed that these autoantibodies in sera of patients with Graves’ disease target the TSH receptor (TSHR) and stimulation of the TSHR by autoantibodies is responsible for thyroid overactivity in Graves’ disease [2]. This key observation resulted in development of the first in vitro receptor binding assay to measure TSHR autoantibodies (TRAb) to help in the diagnosis and management of autoimmune thyroid disease (AITD).

Results

Conclusion