Experimental Reproduction of Dynamic Fluctuation of TSH Receptor–Binding Antibodies Between Stimulation and Inhibition

Tetsuya Tagami, Kaho Hiroshima-Hamanaka, Hironobu Umakoshi, Mika Tsuiki-Naruse, Toru Kusakabe, Noriko Satoh-Asahara, Akira Shimatsu, Kenji Moriyama
Journal of the Endocrine Society, Volume 3, Issue 12, December 2019, Pages 2361–2373
https://doi.org/10.1210/js.2019-00012

Abstract

Context

Hyperthyroidism in Graves disease (GD) is caused by autoantibody stimulation of the TSH receptor (TSHR). TSHR autoantibody (TSHR-Ab) activity is measured routinely by inhibition of labeled ligand (TSH or M22) binding to the TSHR [TSH-binding inhibitory immunoglobulins (TBIIs)] or by stimulation of cAMP production in isolated cells [TSH receptor–stimulating antibodies (TSAbs)]. Usually, measurements of TSHR-Abs by TBIIs agree reasonably well with TSAb values at least in the setting of hyperthyroidism, and both measurements tend to change in parallel during treatment with some exceptions. In this study, we describe three unusual cases, which illustrate nearly pure stimulating, blocking, or neutral properties of TSHR-Abs.

Objective

Whether patient serum TSHR-Abs can be reproduced by mixtures of human monoclonal autoantibodies to the TSHR was studied because the sera in most patients show moderate properties having both of TBII and TSAb activities.

Design

We compared the TBII and TSAb activities of serum from four unusual patients in detail with mixtures of human monoclonal TSHR-Abs (mAbs) M22 (stimulating), K1-18 (stimulating), and K1-70 (blocking).

Results

Characteristic of a patient’s serum was similar to M22 or K1-18, another was similar to K1-70, whereas another was similar to a mixture of K1-70 and M22 (or K1-18). Additionally, some patients seemed to have neutral TSHR-Abs in their sera.

Conclusions

Our studies suggest that the characteristics of TSHR-Abs in the patient serum can be mimicked by mixtures of human mAbs to the TSHR, stimulating, blocking, and neutral if any.

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