Blocking type TSH receptor antibodies

Furmaniak, Jadwiga; Sanders, Jane; Smith, Bernard Rees

doi:10.1007/s13317-012-0028-1

Cited by 49 publications

(39 citation statements)

References 85 publications

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“…Despite these continuing uncertainties, they are the preferred treatment in most parts of the world. While novel pharmacologic approaches that target the autoimmune basis of Graves' disease may be on the horizon (143,144), such therapies will likely be available only to future generations of physicians. In 1945 in his Harvey Lecture (1) Astwood predicted: 'The time will not be long before the common practice of ablating the thyroid will pass into history'.…”

Section: Discussionmentioning

confidence: 99%

Antithyroid drug therapy: 70 years later

Burch

Cooper

2018

European Journal of Endocrinology

100

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The thionamide antithyroid drugs were discovered in large part following serendipitous observations by a number of investigators in the 1940s who found that sulfhydryl-containing compounds were goitrogenic in animals. This prompted Prof. Edwin B Astwood to pioneer the use of these compounds to treat hyperthyroidism in the early 1940s and to develop the more potent and less toxic drugs that are used today. Despite their simple molecular structure and ease of use, many uncertainties remain, including their mechanism(s) of action, clinical role, optimal use in pregnancy and the prediction and prevention of rare but potentially life-threatening adverse reactions. In this review, we summarize the history of the development of these drugs and outline their current role in the clinical management of patients with hyperthyroidism.

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Section: Discussionmentioning

confidence: 99%

Antithyroid drug therapy: 70 years later

Burch

Cooper

2018

European Journal of Endocrinology

100

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“…Several novel therapeutic approaches for human Graves’ disease are being tested including small molecule inhibitors of TSHR function (4,5), monoclonal TSHR antibodies that block the function of thyroid stimulating autoantibodies (TSAb)(6), and inhibitors of components of the adaptive immune system, such as rituximab which target B-lymphocytes (7,8). Most important, however, even if successfully introduced into the pharmacopeia, these approaches may treat, but will not cure Graves’ disease, and non-specific immunological inhibitors have potentially severe side effects.…”

Section: Introductionmentioning

confidence: 99%

Critical Differences between Induced and Spontaneous Mouse Models of Graves’ Disease with Implications for Antigen-Specific Immunotherapy in Humans

Rapoport

Banuelos

Aliesky

et al. 2016

The Journal of Immunology

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Graves’ hyperthyroidism, a common autoimmune disease caused by pathogenic autoantibodies to the thyrotropin (TSH) receptor, can be treated but not cured. This single autoantigenic target makes Graves’ disease a prime candidate for antigen-specific immunotherapy. Previously, in an induced mouse model, injecting TSHR A-subunit protein attenuated hyperthyroidism by diverting pathogenic TSHR antibodies to a non-functional variety. Here we explored the possibility of a similar diversion in a mouse model that spontaneously develops pathogenic TSHR autoantibodies, NOD.H2h4 mice with the human(h) TSHR A-subunit transgene expressed in the thyroid and (shown here) the thymus. We hypothesized that such diversion would occur following injection of “inactive” hTSHR A-subunit protein recognized only by non-pathogenic (not pathogenic) TSHR antibodies. Surprisingly, rather than attenuating the pre-existing pathogenic TSHR level, in TSHR/NOD.H2h4 mice inactive hTSHR antigen injected without adjuvant enhanced the levels of pathogenic TSH-binding inhibition (TBI) and thyroid stimulating antibodies, as well as non-pathogenic antibodies detected by ELISA. This effect was TSHR-specific as spontaneously occurring autoantibodies to thyroglobulin and thyroid peroxidase were unaffected. As controls, non-transgenic NOD.H2h4 mice similarly injected with inactive hTSHR A-subunit protein unexpectedly developed TSHR antibodies, but only of the non-pathogenic variety detected by ELISA. Our observations highlight critical differences between induced and spontaneous mouse models of Graves’ disease with implications for potential immunotherapy in humans. In hTSHR/NOD.H2h4 mice with ongoing disease, injecting inactive hTSHR A-subunit protein fails to divert the autoantibody response to a non-pathogenic form. Indeed, such therapy is likely to enhance pathogenic antibody production and exacerbate Graves’ disease in humans.

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“…These stimulating TRAbs are present in the majority of GD patients. The second TRAbs, named blocking antibodies, occur less often and inhibit receptor activation [40]. Importantly, the main autoantigen that binds to stimulating TRAb is not TSH receptor but its shed A subunit.…”

Section: Prace Poglądowementioning

confidence: 99%

Glycosylation of thyroid-stimulating hormone receptor

Korta

Pocheć

2019

Endokrynologia Polska

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Thyroid-stimulating hormone receptor (TSHR) is a typical membrane receptor with 7-transmembrane helix domain (7TMR), coupled to the G protein. The mature receptor, present in the cell membrane, is composed of the A subunit comprising a large extracellular domain, and the B subunit, which consists of a short extracellular fragment anchored in the cell membrane and an intracellular part. The TSH receptor is subject to numerous post-translational modifications that determine its final structure and significantly affect its activity. One of them is glycosylation. TSHR is abundantly N-glycosylated, due to the presence of six N-glycosylation sites in the extracellular domain (Asn77, Asn99, Asn113, Asn177, Asn198, Asn302), mostly evolutionarily conserved. N-glycans constitute 30-40% of the receptor molecular weight. The glycans are necessary for the receptor trafficking to the plasma membrane and binding of TSH to the receptor. Fucosylated and sialylated N-oligosaccharides were found on TSHR molecules. The increased sialylation of TSHR glycans correlates positively with the receptor binding ability and prolongs the time of receptor incorporation into the cell membrane. TSHR is the main autoantigen in Graves' disease (GD), one of the thyroid autoimmune diseases. One hypothesis assumes that the higher N-glycosylation of THSR in human compared to animals influences the breaking of autotolerance and GD development. N-oligosaccharides are the important part of THSR molecule, necessary for the proper functioning of receptors and probably involved in thyroid autoimmunity in GD.

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Blocking type TSH receptor antibodies

Cited by 49 publications

References 85 publications

Antithyroid drug therapy: 70 years later

Antithyroid drug therapy: 70 years later

Critical Differences between Induced and Spontaneous Mouse Models of Graves’ Disease with Implications for Antigen-Specific Immunotherapy in Humans

Glycosylation of thyroid-stimulating hormone receptor

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