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

2019 ◽  
Vol 3 (12) ◽  
pp. 2361-2373
Author(s):  
Tetsuya Tagami ◽  
Kaho Hiroshima-Hamanaka ◽  
Hironobu Umakoshi ◽  
Mika Tsuiki-Naruse ◽  
Toru Kusakabe ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Camp Production ◽  
Isolated Cells ◽  
Human Mabs ◽  
Experimental Reproduction ◽  
Dynamic Fluctuation ◽  
Stimulation Of

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.

A Drug-like Antagonist Inhibits TSH Receptor-Mediated Stimulation of cAMP Production in Graves’ Orbital Fibroblasts

Thyroid ◽  
2012 ◽  
pp. 120517084830005 ◽  
Author(s):  
Marvin C Gershengorn ◽  
Susanne Neumann ◽  
Arthur Pope ◽  
Elizabeth Geras-Raaka ◽  
Bruce M Raaka ◽  
...  
Keyword(s):  
Tsh Receptor ◽  
Camp Production ◽  
Orbital Fibroblasts ◽  
Stimulation Of

scholarly journals A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor

2011 ◽  
Vol 96 (2) ◽  
pp. 548-554 ◽  
Author(s):  
Susanne Neumann ◽  
Elena Eliseeva ◽  
Joshua G. McCoy ◽  
Giorgio Napolitano ◽  
Cesidio Giuliani ◽  
...  
Keyword(s):  
Small Molecule ◽  
Primary Cultures ◽  
Receptor Activation ◽  
Inverse Agonist ◽  
Tsh Receptor ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Mrna Levels ◽  
Camp Production ◽  
Small Molecule Antagonist

abstract Context: Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD. Objective: Our objective was to develop a better TSHR antagonist and use it to determine whether inhibition of TSAb activation of TSHR is a general phenomenon. Design: We aimed to chemically modify a previously reported small-molecule TSHR ligand to develop a better antagonist and determine whether it inhibits TSHR signaling by 30 GD sera. TSHR signaling was measured in two in vitro systems: model HEK-EM293 cells stably overexpressing human TSHRs and primary cultures of human thyrocytes. TSHR signaling was measured as cAMP production and by effects on thyroid peroxidase mRNA. Results: We tested analogs of a previously reported small-molecule TSHR inverse agonist and selected the best NCGC00229600 for further study. In the model system, NCGC00229600 inhibited basal and TSH-stimulated cAMP production. NCGC00229600 inhibition of TSH signaling was competitive even though it did not compete for TSH binding; that is, NCGC00229600 is an allosteric inverse agonist. NCGC00229600 inhibited cAMP production by 39 ± 2.6% by all 30 GD sera tested. In primary cultures of human thyrocytes, NCGC00229600 inhibited TSHR-mediated basal and GD sera up-regulation of thyroperoxidase mRNA levels by 65 ± 2.0%. Conclusion: NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera.

TSH RECEPTOR BINDING AND THYROID STIMULATION BY SERA FROM PATIENTS WITH GRAVES' DISEASE

1983 ◽  
Vol 19 (3) ◽  
pp. 305-311 ◽  
Author(s):  
J. GINSBERG ◽  
G. SHEWRING ◽  
B. REES SMITH
Keyword(s):  
Receptor Binding ◽  
Tsh Receptor ◽  
Graves Disease

The prognostic value of TSH receptor binding and thyroid stimulating antibodies following antithyroid drug treatment of Graves' disease

1989 ◽  
Vol 121 (5) ◽  
pp. 666-670 ◽  
Author(s):  
R. Wilson ◽  
W. D. Fraser ◽  
J. H. McKillop ◽  
J. A. Thomson
Keyword(s):  
Receptor Binding ◽  
Antithyroid Drug ◽  
Tsh Receptor ◽  
Assay Method ◽  
Graves Disease ◽  
Receptor Antibody ◽  
Tsh Receptor Antibody ◽  
Thyroid Stimulating Antibodies ◽  
Antithyroid Drug Treatment ◽  
Antibody Levels

Abstract. Following a course of medical therapy for Graves' disease approximately 50% of patients relapse. Previous studies have tried to identify these patients by measuring antibodies to the TSH receptor using a range of assay methods. Such studies have produced widely discrepant results. The aim of the present study was to compare the accuracy with which TSH receptor binding antibodies and thyroid-stimulating antibodies could identify cases of relapse and remission. Fifty-six newly diagnosed and previously untreated Graves' disease patients were recruited into the study. At presentation 4 were negative for TSH receptor antibody and 5 negative for TS-ab. The remaining 47 were positive for TSH receptor antibody and TS-ab although correlation of the degree of abnormality between methods was poor (r = 0.13 NS). After 12 months carbimazole treatment 28 patients relapsed during the following year and 19 remained in remission. TSH receptor antibody levels obtained at the end of a 12-month course of treatment correctly identified 93% who relapsed and 95% who remained in remission. TS-ab levels could only correctly identify 68% who relapsed and 53% who remained in remission. These results have shown that the accuracy with which patients likely to relapse can be identified depends on the assay method chosen which may account for some of the discrepancies found in previously published studies.

Evidence of a correlation between thyrotrophin receptor binding inhibition and thyroid adenylate cyclase activation by immunoglobulins in Graves' disease before and during long-term antithyroid treatment

1982 ◽  
Vol 101 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Henning Bliddal ◽  
Karine Bech ◽  
Per Hyltoft Petersen ◽  
Kaj Siersbæk-Nielsen ◽  
Thorkild Friis
Keyword(s):  
Adenylate Cyclase ◽  
Statistical Model ◽  
Receptor Binding ◽  
Graves Disease ◽  
Adenylate Cyclase Activation ◽  
Binding Inhibition ◽  
Antithyroid Treatment ◽  
Analytical Variation ◽  
Stimulation Of

Abstract. In the present study we have measured in parallel thyrotrophin binding inhibiting immunoglobulins (TBII) and thyroid adenylate cyclase stimulating immunoglobulins (TACSI) in patients with Graves' disease (GD) both before and during long-term antithyroid treatment. A statistical model based on the calculation of the differences (TACSI-TBII) is presented, comparing the changes in this parameter to the analytical variation. The correlation between TBII and TACSI in 52 patients with GD before treatment was: r = 0.58, P < 0.0001. During long-term antithyroid treatment of GD the 2 activities changed in parallel in 39 of 45 patients followed. In a few patients discrepancies were observed, and 1 patient, initially TACSI positive, developed adenylate cyclase inhibiting IgG during treatment but without detectable TBII. In conclusion, 1) TBII and TACSI are significantly correlated in patients with GD both before and during long-term antithyroid treatment, 2) in some patients discrepancies between TBII and TACSI suggest, that these IgGs are heterogeneous with varying capacity for stimulation of the adenylate cyclase and receptor binding, and 3) adenylate cyclase inhibitory IgG without TBII activity was demonstrated in GD.

Relevance of TSH-Receptor stimulating and blocking autoantibody measurement for the prediction of relapse in Graves' disease

2005 ◽  
Vol 113 (S 1) ◽  
Author(s):  
M Schott ◽  
WB Minich ◽  
C Papewalis ◽  
J Seissler ◽  
WA Scherbaum ◽  
...  
Keyword(s):  
Tsh Receptor ◽  
Graves Disease ◽  
Prediction Of Relapse
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