Genetics and epigenetics of autoimmune thyroid diseases: Translational implications

Lee, Hanna J.; Stefan-Lifshitz, Mihaela; Li, Cheuk Wun; Tomer, Yaron

doi:10.1016/j.beem.2022.101661

Cited by 33 publications

(21 citation statements)

References 97 publications

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“…Several aspects still need to be clarified: (i) Is this mouse model reliably recapitulating the human scenario of development of autoimmune thyroid diseases, known to have a strong component of genetic predisposition and gender dependence? [ 85 , 86 ]; (ii) Does the development of autoimmune thyroid diseases (AITD) require a long term disbalance of thyroid function and its interaction with an activated immune system? (iii) Might relatively short-lived mice not adequately mimic such a disease history, although various mouse models have been developed which replicate many but not all aspects of human AITD?…”

Section: Selenoproteinsmentioning

confidence: 99%

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Köhrle

2023

IJMS

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The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus–pituitary–thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as ‘thyroxisome’ at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

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Section: Selenoproteinsmentioning

confidence: 99%

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Köhrle

2023

IJMS

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“…Several genetic signatures remain candidates as the basis for susceptibility to GD. 4,5 Polymorphisms of the thyroid stimulating hormone, thyrotropin (TSH) receptor (TSHR), CTLA-4, CD25, thyroglobulin, Human leukocyte antigen class II histocompatibility antigen, DRB1 beta chain-Arg74, CD40, and Tyrosine-protein phosphatase non-receptor22 are among these. An open question concerns whether genetic determinants for GD might differ from those for TAO.…”

Section: Genetic and Acquired Factors Promoting Gd And Taomentioning

confidence: 99%

Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy

Smith

2023

Ophthalmic Plastic &Amp; Reconstructive Surgery

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Purpose: Review the historical context of research and changing therapeutic landscape of thyroid-associated ophthalmopathy (TAO) by focusing on the relationship between TAO, CD34+ fibrocytes, thyrotropin receptor (TSHR), and insulin-like growth factor-I receptor (IGF-IR). Methods: A literature review using search terms, including fibrocytes, IGF-IR, TSHR, TAO, and thyroid eye disease. Results: The mechanisms involved in TAO have been partially identified. Substantial progress has been made over several decades, including 1) recognizing the interplay between the professional immune system and orbital tissues; 2) TSHR and IGF-IR act interdependently in mediating the pathogenesis of TAO; 3) Multiple cytokines and specific immune cells are involved in activating and remodeling orbital tissue; 4) Recognition of these mechanisms is allowing the development of target therapies such as teprotumumab, a monoclonal antibody IGF-IR inhibitor approved by the US Food and drug administration for treatment of TAO; and 5) It appears that teprotumumab acts on the systemic immune system peripheral to the orbit. Conclusion: Additional molecules targeting IGF-IR and other plausible disease mechanisms are currently under development. This activity in the TAO therapeutic space portends even greater improvements in patient care.

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“…Je größer die Anzahl der betroffenen Mitglieder, umso größer ist das Risiko und desto früher die Krankheitsmanifestation. Es finden sich Assoziationen zu schilddrüsenspezifischen Genen (Tg, TSHR) und zu Genen, die für die Reaktionen des Immunsystems eine Rolle spielen (FOXP3, CD25, CD40, CTLA-4, HLA), wobei HLA-DR3 das höchste Risiko trägt [30,31]. 2…”

Section: Risikofaktorenunclassified

“…The greater the number of affected family members, the greater the risk and the earlier the disease onset. Associations have been identified with thyroid-specific genes (Tg, TSH-R) and genes that play a role in immune responses (FOXP3, CD25, CD40, CTLA-4, HLA), whereby HLA-DR3 is associated with the highest risk 30 , 31 .…”

Section: Risk Factorsmentioning

confidence: 99%

Aktuelle Therapieansätze der endokrinen Orbitopathie – sind die zielgerichteten Therapien die Zukunft?

Eckstein,

Stöhr,

Görtz

et al. 2023

Klin Monbl Augenheilkd

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Die Endokrine Orbitopathie (EO) ist eine Autoimmunerkrankung der Augenhöhle die am allerhäufigsten im Zusammenhang mit einer Schilddrüsenautoimmunerkrankung vom Typ Basedow auftritt. Für die Diagnose spezifisch und für die Pathogenese von zentraler Bedeutung ist das Auftreten von gegen den TSH-Rezeptor gerichteten Autoantikörpern (TRAK). Diese Autoantikörper, zumeist mit stimulierender Wirkung, induzieren eine unkontrollierte Schilddrüsenüberfunktion und in der Augenhöhle einen Gewebeumbau und eine mehr oder weniger ausgeprägte Entzündung. In Folge kommt es im variablen Ausmaß zu entzündlicher Schwellung periokulär, Exophthalmus, und Fibrose der Augenmuskeln und dadurch zu einer Störung der symmetrischen Augenbeweglichkeit mit Doppelbildwahrnehmung. In den letzten Jahrzehnten umfassten die therapeutischen Anstrengungen für die entzündliche Orbitopathie allgemein immunsuppressive Maßnahmen und für die Schilddrüsenüberfunktion die symptomatische Therapie durch Hemmung der Schilddrüsenhormonproduktion. Mit dem Bekanntwerden, dass durch die TRAK auch ein wichtiger Wachstumsfaktorrezeptor aktiviert wird, der IGF1R (Insulin like growth factor 1 Rezeptor), wurden Biologika entwickelt, die diesen blockieren. Teprotumumab ist bereits in den USA zugelassen und die Therapieeffekte sind v.a. hinsichtlich der Exophthalmusreduktion enorm. Nebenwirkungen, v.a. Hyperglykämie und Hörstörungen sind zu beachten. Inwieweit die Autoimmunreaktionen (Produktion der TRAK/Anlocken von immunkompetenten Zellen) durch diese Therapien auch beeinflusst werden, ist noch nicht ausreichend geklärt. Rezidive nach der Therapie zeigen, dass die Hemmung der Autoimmunreaktion im Therapiekonzept insbesondere bei schwerem Verlauf mit enthalten sein muss. Graves’ orbitopathy is an autoimmune disease of the orbit that occurs most frequently with Graves’ hyperthyroidism. The occurrence of autoantibodies directed against the TSH receptor (TRAb) is of central importance for the diagnosis and for the pathogenesis. These autoantibodies, mostly with a stimulating effect, induce uncontrolled hyperthyroidism and tissue remodelling in the orbit and a more or less pronounced inflammation. Consequently, patients suffer in a variable extent from periocular swelling, exophthalmos, and fibrosis of the eye muscles and thus a restrictive motility impairment with double vision. In recent decades, therapeutic efforts mainly comprised immunosuppressive treatments and antithyroid drug therapy for hyperthyroidism to inhibit thyroid hormone production. With the detection that TRAb also activates an important growth factor receptor, IGF1R (insulin-like growth factor 1 receptor), biological agents have been developed. Teprotumumab (an inhibitory IGF1R antibody) has already been approved in the USA and the therapeutic effects are enormous, especially with regard to the reduction of exophthalmos. Side effects are to be considered, especially hyperglycaemia and hearing loss. If the autoimmune reaction (development of the TRAb/attraction of immunocompetent cells) is also influenced by anti IGF1R inhibiting agents, has yet to be sufficiently clarified. Recurrences after therapy show, that the inhibition of the antibody development must be included in the therapeutic concept, especially in severe cases.

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Genetics and epigenetics of autoimmune thyroid diseases: Translational implications

Cited by 33 publications

References 97 publications

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy

Aktuelle Therapieansätze der endokrinen Orbitopathie – sind die zielgerichteten Therapien die Zukunft?

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