Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves’ disease

Costagliola, Sabine; Many, Marie‐Christine; Denef, Jean François; Pohlenz, Joachim; Refetoff, Samuel; Vassart, Gilbert

doi:10.1172/jci7665

Cited by 153 publications

(133 citation statements)

References 34 publications

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“…The TSHRAb production in susceptible individuals could thus be induced by the destruction of thyroid follicles that occurs during the course of thyroiditis, regardless of their cause. In animal models, immunization with TSH receptor cDNA is able to induce production of TSHRAbs and even hyperthyroidism in some cases (20). Treatment with IFN-a might be a major sensitizing factor in this autoimmunization-like spontaneous immunostimulation of the postpartum period or immune restoration in successfully treated HIV-infected patients (21), situations which have recently been associated with the occurrence of Graves' disease.…”

Section: Discussionmentioning

confidence: 99%

Interferon-α-induced hyperthyroidism: a three-stage evolution from silent thyroiditis towards Graves’ disease

et al. 2006

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Autoimmune thyroid disease is a common side-effect of interferon-a (IFN-a) treatment of viral hepatitis C. We have described three patients with hepatitis C for whom IFN-a and ribavirin were prescribed and who developed two successive phases of silent thyroiditis followed by hyperthryroidism relapse due to Graves' disease. These three men had no known history of familial or personal thyroid disease. Destructive thyrotoxicosis appeared 4-6 months after starting IFN-a, followed by Graves' hyperthyroidism within 8 to11 months. The thyrotropin (TSH) level was normal before IFN-a was started. The diagnosis of destructive thyroiditis was confirmed by anti-TSH receptor antibody (TSHRAb) negativity and the absence of radionuclide ( 123 I or 99 Tc) uptake on thyroid scintiscans. Eight to eleven months after starting treatment, TSHRAb positivity and intense scintigraphic uptake confirmed the appearance of Graves' disease. IFN-a was continued in only one patient. Hence, hyperthyroidism induced by IFN-a could correspond to the first phase of silent thyroiditis, to Graves' disease or to the succession of both. Rigorous diagnostic procedures with repeated scintiscans and TSHRAb titering are necessary to avoid a false diagnosis and inappropriate therapy.

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Section: Discussionmentioning

confidence: 99%

Interferon-α-induced hyperthyroidism: a three-stage evolution from silent thyroiditis towards Graves’ disease

et al. 2006

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“…Thyroiditis can be induced in several mouse strains in association with a Th1 response by conventional immunization with bacterial TSHR ectodomain and adjuvant [30] or following transfer of TSHR-primed splenocytes [6]. Very recently, it was reported that TSHR antibodies and thyroiditis develop following TSHR-DNA vaccination in a subset of outbred mice [31]. Whether or not the novel approaches to induce a Graves'-like disease (genetic immunization or injection of TSHR-expressing cells) require a Th2-type response for the development of thyroiditis remains unanswered.…”

Section: Discussionmentioning

confidence: 99%

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Yan

Guo

Pichurin

et al. 2000

Clinical and Experimental Immunology

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SUMMARYAKR/N mice injected with fibroblasts expressing MHC class II (RT4.15HP cells) and the TSH receptor (TSHR) develop antibodies similar to those in Graves' disease. We were unable to analyse the subclass of these antibodies because of unexpectedly high non-specific binding by ELISA or flow cytometry. The non-specific binding reflected generalized immune activation which occurred even when the fibroblasts did not express the TSHR. However, the IgG subclasses were determined for thyroid peroxidase (TPO) antibodies induced using TPO-expressing RT4.14HP cells and found to be IgG2a . IgG1. This Th1 pattern is consistent with spontaneous secretion of interferon-gamma (but not IL-4 or IL-10) by splenocytes from injected mice. The Th1 bias was related to fibroblast injection because conventional immunization of the same mouse strain with purified TPO and adjuvant induced a Th2 response (IgG1 .. IgG2a). Further, untransfected fibroblasts themselves induced powerful, non-specific proliferative responses when used as antigen-presenting cells (APC) in vitro. Flow cytometry revealed that the RT4.15HP fibroblasts (and TSHR-and TPO-transfected derivatives) expressed B7-1. Unexpected constitutive expression of this key molecule may bypass the requirement for up-regulation of other costimulatory molecules involved in T cell stimulation. Our data support the concept that RT4.15HP fibroblasts present the TSHR (or TPO), at least for initiating the immune response. However, the accompanying generalized immune stimulation creates difficulties for analysis of TSHR-specific T and B lymphocytes. On the other hand, extension of the model to TPO, an easier antigen to study, will facilitate analysis of murine T cell responses likely to resemble those in human thyroid autoimmunity.

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“…This receptor has received considerable attention as a potential autoantigen relevant to TAO, and has been detected widely in cells of the fibroblast lineage (37,38) and in several adipose tissue depots (39,40). Recently, animal models of GD have been described, involving mouse immunization with the TSHR, its cDNA, or by passively transferring TSHR-primed T cells (41)(42)(43). These animals variably exhibit hyperthyroidism and thyroid histopathology consistent with the disease.…”

Section: Igs From Patients With Graves' Disease Induce the Expressionmentioning

confidence: 99%

“…These animals variably exhibit hyperthyroidism and thyroid histopathology consistent with the disease. Some of these reports contain histological evidence for infiltrative tissue changes and Th2 cytokine profiles in the orbits and edema of the extraocular muscles in animals manifesting TSHR-induced thyroiditis (42,43). A potentially important relationship between circulating Igs directed against TSHR and the extrathyroidal manifestations of GD is implied by the presence of anti-TSHR Abs in patients with TAO (44).…”

Section: Igs From Patients With Graves' Disease Induce the Expressionmentioning

confidence: 99%

Igs from Patients with Graves’ Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts

Pritchard

Horst

Cruikshank

et al. 2002

The Journal of Immunology

156

143

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Thyroid-associated ophthalmopathy and dermopathy are connective tissue manifestations of Graves’ disease (GD). Tissue remodeling is a prominent feature of both and is apparently driven by recruited T cells. In this study, we report that IgG isolated from patients with GD (GD-IgG) up-regulates T lymphocyte chemoattractant activity in GD-derived fibroblasts from orbit, thyroid, and several regions of skin. This chemoattractant activity, absent in fibroblasts from donors without known thyroid disease, is partially susceptible to neutralization by anti-IL-16 and anti-RANTES Abs. IL-16 is a CD4+-specific chemoattractant and RANTES is a C-C-type chemokine. IL-16 and RANTES protein levels, as determined by specific ELISAs, are substantially increased by GD-IgG in GD fibroblasts. Addition of the macrolide, rapamycin, to fibroblast culture medium blocked the up-regulation by GD-IgG of IL-16, implicating the FRAP/mTOR/p70s6k pathway in the induction of IL-16 expression. These findings suggest a specific mechanism for activation of fibroblasts in GD resulting in the recruitment of T cells. They may provide insight into a missing link between the glandular and extrathyroidal manifestations of GD.

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Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves’ disease

Cited by 153 publications

References 34 publications

Interferon-α-induced hyperthyroidism: a three-stage evolution from silent thyroiditis towards Graves’ disease

Interferon-α-induced hyperthyroidism: a three-stage evolution from silent thyroiditis towards Graves’ disease

Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens

Igs from Patients with Graves’ Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts

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