Expression of thyrotropin receptors in rat thymus

Murakami, Masami; Hosoi, Yasuhiro; Araki, Osamu; Morimura, Tadashi; Imamura, Makoto; Ogiwara, Takayuki; Mizuma, Haruo; Mori, Masataka

doi:10.1016/s0024-3205(01)01077-3

Cited by 21 publications

(15 citation statements)

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“…The TSHR is expressed at low levels in human and rodent thymic tissue (37)(38)(39) and likely plays a role in central tolerance in wild-type mice. Thyroglobulin is expressed in the thymus (for example, see Refs.…”

Section: Discussionmentioning

confidence: 99%

Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization

Pichurin

Chen

Chazenbalk

et al. 2006

The Journal of Immunology

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The thyrotropin receptor (TSHR), the major autoantigen in Graves’ disease, is posttranslationally modified by intramolecular cleavage to form disulfide-linked A- and B-subunits. Because Graves’ hyperthyroidism is preferentially induced in BALB/c mice using adenovirus encoding the free A-subunit rather than full-length human TSHR, the shed A-subunit appears to drive the disease-associated autoimmune response. To further investigate this phenomenon, we generated transgenic mice with the human A-subunit targeted to the thyroid. Founder transgenic mice had normal thyroid function and were backcrossed to BALB/c. The A-subunit mRNA expression was confirmed in thyroid tissue. Unlike wild-type littermates, transgenic mice immunized with low-dose A-subunit adenovirus failed to develop TSHR Abs, hyperthyroidism, or splenocyte responses to TSHR Ag. Conventional immunization with A-subunit protein and adjuvants induced TSHR Abs lacking the characteristics of human autoantibodies. Unresponsiveness was partially overcome using high-dose, full-length human TSHR adenovirus. Although of low titer, these induced Abs recognized the N terminus of the A-subunit, and splenocytes responded to A-subunit peptides. Therefore, “non-self” regions in the B-subunit did not contribute to inducing responses. Indeed, transgenic mice immunized with high-dose A-subunit adenovirus developed TSHR Abs with thyrotropin-binding inhibitory activity, although at lower titers than wild-type littermates, suggesting down-regulation in the transgenic mice. In conclusion, in mice expressing a human A-subunit transgene in the thyroid, non-self human B-subunit epitopes are not necessary to induce responses to the A-subunit. Our findings raise the possibility that autoimmunity to the TSHR in humans may not involve epitopes on a cross-reacting protein, but rather, strong adjuvant signals provided in bystander immune responses.

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Section: Discussionmentioning

confidence: 99%

Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization

Pichurin

Chen

Chazenbalk

et al. 2006

The Journal of Immunology

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“…In 1988, 74 years after its clinical description, an autoimmune mechanism for thymic hyperplasia was suggested, by demonstrating that IgG from one patient with GD could stimulate thymocyte mitogenesis in vitro [109]. Most remarkably, TSHR was found expressed in total human thymus tissue extracts [110], and in thymic rat epithelial cells [111]. Since then, an increasing number of studies confirmed that TSHR is expressed in the thymus [89,107,112,113].…”

Section: Tshr In the Thymus And Its Possible Dual Role In Gd ▼mentioning

confidence: 99%

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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“…Although the TSH-R is traditionally thought to be expressed exclusively within the pituitary and the thyroid gland, several studies have now identified novel functions for TSH and TSH-R signaling in various organ systems, including the immune system. TSH-R expression has been described in human (17,18) and rat thymus (19), as well as in several other hematopoietic cell types (20,21), albeit without identification of specific subpopulations. Moreover, a clear association has been described between Graves' disease and thymic hyperplasia (18), characterized mainly by an increase in developing thymocytes (22).…”

Section: Introductionmentioning

confidence: 99%

Thyrotropin Acts as a T-Cell Developmental Factor in Mice and Humans

Weerd

Hagen

Schrijver

et al. 2014

Thyroid

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Using gene expression profiling, we detected differential thyrotropin receptor (TSH-R) expression during human T-cell development in the thymus. This expression pattern indicated a potential role for the TSH-R within the thymus, independent of its function in the thyroid gland. Here, we demonstrate that TSH-R expression is thymus-specific within the immune system. TSH was able to bind and activate the TSH-R present on thymocytes, thereby activating calcium signaling and cyclic adenosine monophosphate signaling pathways. Mice lacking functional TSH-R expression (hyt/hyt mice) were shown to have lower frequencies of DP and SP thymocytes compared to their heterozygous littermates. Moreover, addition of TSH to co-cultures of human thymocytes enhanced T-cell development. Thus, TSH acts as a previously unrecognized growth factor for developing T cells, with potential clinical use to enhance thymic output and thereby the functional T-cell repertoire in the periphery. The direct effects of TSH on thymocytes may also explain the thus far enigmatic thymic hyperplasia in Graves' disease.

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Expression of thyrotropin receptors in rat thymus

Cited by 21 publications

References 0 publications

Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization

Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization

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

Thyrotropin Acts as a T-Cell Developmental Factor in Mice and Humans

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