Thyroid-Stimulating Antibody Mimics Thyrotropin in Its Ability to Desensitize the Adenosine 3′,5′- Monophosphate Response to Acute Stimulation in Continuously Cultured Rat Thyroid Cells (FRT-L5)*

Vitti, Paolo; Chiovato, Luca; Ceccarelli, P.; Lombardi, Antonio; Novaes, M. A. S.; Fenzi, G. F.; Pinchera, Aldo

doi:10.1210/jcem-63-2-454

Cited by 18 publications

(2 citation statements)

References 20 publications

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“…Assays were performed in triplicate for each experiment. Extracellular cAMP accumulation in the medium was determined using an in-house radioimmunoassay method using a commercial polyclonal anti-CAMP Ab, as previously described (29). Results were expressed as the fold-increase of cAMP released in the extracellular medium over the basal value.…”

Section: Measurement Of Tsab Activity In Human Iggs Using Jpo9 Cellsmentioning

confidence: 99%

Graves’ Disease TSHR-Stimulating Antibodies (TSAbs) Induce the Activation of Immature Thymocytes: A Clue to the Riddle of TSAbs Generation?

Giménez‐Barcons

Colobran

Gómez-Pau

et al. 2015

The Journal of Immunology

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Graves’ disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.

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Section: Measurement Of Tsab Activity In Human Iggs Using Jpo9 Cellsmentioning

confidence: 99%

Graves’ Disease TSHR-Stimulating Antibodies (TSAbs) Induce the Activation of Immature Thymocytes: A Clue to the Riddle of TSAbs Generation?

Giménez‐Barcons

Colobran

Gómez-Pau

et al. 2015

The Journal of Immunology

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“…TSHR desensitization has been extensively studied in thyroid cells following TSH stimulation (19)(20)(21)(22)(23). TSHR desensitization, but not downregulation, by TSHR-Ab's from Graves patients' sera has also been documented in vitro (24)(25)(26). However, the clinical relevance of such TSHR-Abinduced inactivation in Graves disease is unclear, since the disease results from sustained overstimulation of the TSHR.…”

Section: Introductionmentioning

confidence: 99%

Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody

Ando¹,

Latif²,

Davies³

2004

J. Clin. Invest.

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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 (TSHRAb's) in Graves disease patients may provide a functional explanation for the poor correlation between thyroid function and serum TSHR-Ab concentrations.

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Endocrinology1

Vogel

Schölkens

et al. 2002

Drug Discovery and Evaluation

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Thyroid-Stimulating Antibody Mimics Thyrotropin in Its Ability to Desensitize the Adenosine 3′,5′- Monophosphate Response to Acute Stimulation in Continuously Cultured Rat Thyroid Cells (FRT-L5)*

Cited by 18 publications

References 20 publications

Graves’ Disease TSHR-Stimulating Antibodies (TSAbs) Induce the Activation of Immature Thymocytes: A Clue to the Riddle of TSAbs Generation?

Graves’ Disease TSHR-Stimulating Antibodies (TSAbs) Induce the Activation of Immature Thymocytes: A Clue to the Riddle of TSAbs Generation?

Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody

Endocrinology1

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