Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Stefan, Mihaela; Wei, Chengguo; Lombardi, Angela; Li, Cheuk Wun; Concepcion, Erlinda; Inabnet, William B.; Owen, Randall P.; Zhang, Weijia; Tomer, Yaron

doi:10.1073/pnas.1408821111

Cited by 80 publications

(68 citation statements)

References 37 publications

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“…Additionally, we also demonstrated that the thyroid transcription factor 1 TTF1 (also known as NK2 homeobox 1, NKX2-1), which activates TSHR transcription in the thyroid gland [106], was not expressed in the thymus. This finding supported the concept that regulation of tissue-restricted antigens gene expression in the thymus is controlled by different mechanisms than in the primary tissue.…”

Section: Reviewmentioning

confidence: 77%

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

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As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.

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Section: Reviewmentioning

confidence: 77%

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

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“…86 Accordingly, deregulation of TSHR-mediated regulatory activity of gene expression, through the inhibition of its transcriptional repressor promyelocytic leukemia zinc finger protein in the thymus, triggers thyroid auto immunity due to the escape of TSHR-reactive T cells from negative selection. 87 Additionally, TRH, which encodes prothyrotropin-releasing hormone, is also transcribed in the thymus of the rat. 88 Given the local production of prothyrotropin-releasing hormone, the intrathymic expression of the thyrotropin receptor and the fact that this neuropeptide is able to enhance thymocyte proliferation, 89,90 an autocrine/paracrine circuit mediated by thyrotropin receptor might control the thymus physiology.…”

Section: Leptinmentioning

confidence: 99%

Hormonal control of T-cell development in health and disease

et al. 2015

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The physiology of the thymus, the primary lymphoid organ in which T cells are generated, is controlled by hormones. Data from animal models indicate that several peptide and nonpeptide hormones act pleiotropically within the thymus to modulate the proliferation, differentiation, migration and death by apoptosis of developing thymocytes. For example, growth hormone and prolactin can enhance thymocyte proliferation and migration, whereas glucocorticoids lead to the apoptosis of these developing cells. The thymus undergoes progressive age-dependent atrophy with a loss of cells being generated and exported, therefore, hormone-based therapies are being developed as an alternative strategy to rejuvenate the organ, as well as to augment thymocyte proliferation and the export of mature T cells to peripheral lymphoid organs. Some hormones (such as growth hormone and progonadoliberin-1) are also being used as therapeutic agents to treat immunodeficiency disorders associated with thymic atrophy, such as HIV infection. In this Review, we discuss the accumulating data that shows the thymus gland is under complex and multifaceted hormonal control that affects the process of T-cell development in health and disease.

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“…The absence of HCV clearance from thyrocytes perpetuates the chronic inflammation and autoimmunity. a-IFN triggers AITD through an epigenetic mechanism involving variant of Tg and TSHr gene promoter [101,102] . Moreover, a-IFN locally enhances the expression of TSH-r, Tg, TPO and HLA class Ⅰ molecules on thyrocytes and the secretion of the potent proinflammatory IL-2 cytokine [11] .…”

Section: Development Of Aitd During the A-ifn Treatment For Hcv Chronmentioning

confidence: 99%

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

Pastore¹

2016

WJH

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The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential crossreaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.

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Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Cited by 80 publications

References 37 publications

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

Hormonal control of T-cell development in health and disease

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

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