The cardiac calsequestrin gene (CASQ2) is up-regulated in the thyroid in patients with Graves’ ophthalmopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Leon Wescombe
PROVIDER: E-GEOD-9340 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Thyroid-associated ophthalmopathy (TAO) is a complex eye and orbital disorder that is uniquely linked to Graves’ hyperthyroidism (GH). A popular explanation for the development of orbital inflammation in these patients is autoimmunity against the TSH-receptor expressed in orbital preadipocytes. However, this has not been proven and alternative hypotheses should be entertained. We have shown recently that antibodies against highly purified rabbit skeletal muscle calsequestrin are sensitive and specific markers of eye muscle inflammation in patients with thyroid autoimmunity. Keywords: disease state comparison
2007-10-16 | GSE9340 | GEO
Project description:Graves’ disease is characterized by goiter, palpitation and exophthalmos (Merseburg’s trias). However, a few patients develop exophthalmos even though their thyroid function is normal, a condition known as euthyroid Graves’ disease (EGD). It remains unknown why these patients remain euthyroid, even though they have potent thyroid-stimulating antibody (TSAb). To investigate whether the immunoglobulins (IgGs) obtained from EGD patients elicit thyroid hormone-releasing activity (THRA), thyroid follicles obtained from Graves’ patients were cultured in agarose-coated culture dishes, and 125I incorporated into the thyroid follicles and organic 125I (mainly de novo-synthesized 125I-T3+125I-T4) released into the culture medium by TSH or purified IgGs were determined as thyroid hormone-releasing activity (THRA). This thyroid follicle culture system allows maintenance of the Wolff-Chaikoff effect, and the expression of mRNA for the sodium-iodide symporter is decreased by high concentrations of iodide (10-6-10-4M) and therapeutic concentrations of amiodarone (1-2microM). hTSH elicited THRA most efficiently at 0.4-10 microU/ml, suggesting that thyroid function is controlled within the normal range of TSH concentration (0.4-4.0 microU/ml). All IgGs obtained from hyperthyroid Graves’ patients elicited THRA equivalent to more than 4.6 microU/ml hTSH. IgGs obtained from EGD patients also had potent THRA, whereas IgGs obtained from normal subjects and Graves’ patients in complete remission had no significant THRA. When thyroid follicles from Graves’ thyroid, into which a number of lymphocytes had infiltrated, were used, only slight THRA was elicited by bTSH or Graves’ IgGs, probably due to inflammatory cytokines produced by immunocompetent cells that could not be separated during gentle centrifugation. Indeed, when thyroid follicles were cultured with autologous intrathyroidal lymphocytes, interleukin-2 completely abolished TSH-induced THRA. When thyroid follicles were cultured with inflammatory cytokines (interleukin-1, tumor-necrosis factor-alpha, or interferon-gamma), each cytokine inhibited TSH-induced THRA in a concentration-dependent manner. These cytokines at lower concentrations synergistically and completely inhibited TSH-induced THRA. Microarray analyses of thyroid follicles cultured with IL-1alpha, TNF-alpha, or INF-gamma revealed decreased expression of mRNAs for TSHR, NIS, TPO and thyroglobulin, accompanied by increased expression of mRNAs for chemokines and cytokines. These findings suggest that IgGs obtained from patients with EGD have potent THRA in vitro, whereas in vivo, these IgGs are unable to elicit biological activity in the thyroid gland. Presumably, immunocompetent cells that infiltrate the thyroid gland produce inflammatory cytokines that synergistically inhibit thyroid function. Since a similar phenomenon may occur in the retroorbital tissues, these patients may develop exophthalmos despite having a normal serum level of TSH. This data will be published in Hyperthyroidism: Etiology, Diagnosis and Treatment (editor-in-chief;Dr.Frank Clumbus,Nova Science Publishers, Inc, New York, USA) Experiment Overall Design: One conditioned experiments: control vs. IL-1 alpha 5ng/ml, cultured for 24 hours; control vs. TNF alpha 20ng/ml, cultured for 24 hours; control vs. IFN gamma 1000U/ml, cultured for 48 hours.
2009-05-01 | E-GEOD-15838 | biostudies-arrayexpress
Project description:Graves’ disease is characterized by goiter, palpitation and exophthalmos (Merseburg’s trias). However, a few patients develop exophthalmos even though their thyroid function is normal, a condition known as euthyroid Graves’ disease (EGD). It remains unknown why these patients remain euthyroid, even though they have potent thyroid-stimulating antibody (TSAb). To investigate whether the immunoglobulins (IgGs) obtained from EGD patients elicit thyroid hormone-releasing activity (THRA), thyroid follicles obtained from Graves’ patients were cultured in agarose-coated culture dishes, and 125I incorporated into the thyroid follicles and organic 125I (mainly de novo-synthesized 125I-T3+125I-T4) released into the culture medium by TSH or purified IgGs were determined as thyroid hormone-releasing activity (THRA). This thyroid follicle culture system allows maintenance of the Wolff-Chaikoff effect, and the expression of mRNA for the sodium-iodide symporter is decreased by high concentrations of iodide (10-6-10-4M) and therapeutic concentrations of amiodarone (1-2microM). hTSH elicited THRA most efficiently at 0.4-10 microU/ml, suggesting that thyroid function is controlled within the normal range of TSH concentration (0.4-4.0 microU/ml). All IgGs obtained from hyperthyroid Graves’ patients elicited THRA equivalent to more than 4.6 microU/ml hTSH. IgGs obtained from EGD patients also had potent THRA, whereas IgGs obtained from normal subjects and Graves’ patients in complete remission had no significant THRA. When thyroid follicles from Graves’ thyroid, into which a number of lymphocytes had infiltrated, were used, only slight THRA was elicited by bTSH or Graves’ IgGs, probably due to inflammatory cytokines produced by immunocompetent cells that could not be separated during gentle centrifugation. Indeed, when thyroid follicles were cultured with autologous intrathyroidal lymphocytes, interleukin-2 completely abolished TSH-induced THRA. When thyroid follicles were cultured with inflammatory cytokines (interleukin-1, tumor-necrosis factor-alpha, or interferon-gamma), each cytokine inhibited TSH-induced THRA in a concentration-dependent manner. These cytokines at lower concentrations synergistically and completely inhibited TSH-induced THRA. Microarray analyses of thyroid follicles cultured with IL-1alpha, TNF-alpha, or INF-gamma revealed decreased expression of mRNAs for TSHR, NIS, TPO and thyroglobulin, accompanied by increased expression of mRNAs for chemokines and cytokines. These findings suggest that IgGs obtained from patients with EGD have potent THRA in vitro, whereas in vivo, these IgGs are unable to elicit biological activity in the thyroid gland. Presumably, immunocompetent cells that infiltrate the thyroid gland produce inflammatory cytokines that synergistically inhibit thyroid function. Since a similar phenomenon may occur in the retroorbital tissues, these patients may develop exophthalmos despite having a normal serum level of TSH. This data will be published in Hyperthyroidism: Etiology, Diagnosis and Treatment (editor-in-chief;Dr.Frank Clumbus,Nova Science Publishers, Inc, New York, USA)
2009-04-28 | GSE15838 | GEO
Project description:Activation of thyroid stimulating hormone receptor (TSHR) fundamentally leads to hyperthyroidism. To elucidate TSHR signaling, we conducted transcriptome analyses for hyperthyroid mice that we generated by overexpressing TSH. TSH overexpression drastically changed their thyroid transcriptome. In particular, enrichment analyses identified the cell cycle, phosphatidylinositol-3 kinase/Akt pathway, and Ras-related protein 1 pathway as possibly associated with goiter development. Regarding hyperthyroidism, Slc26a4 was exclusively upregulated with TSH overexpression among genes crucial to thyroid hormone secretion. To verify its significance, we overexpressed TSH in Slc26a4 knockout mice. TSH overexpression caused hyperthyroidism in Slc26a4 knockout mice, equivalent to that in control mice. Thus, we did not observe significant changes in known genes and pathways involved in thyroid hormone secretion with TSH overexpression. Our datasets might include candidate genes that have not yet been identified as regulators of thyroid function. Our transcriptome datasets regarding hyperthyroidism can contribute to future research on TSHR signaling.
2024-10-21 | GSE279577 | GEO
Project description:The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including d thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show for the first time, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease. CD40 in Thyroid Autoimmunity: 1) Incubation of human thyroid cells with G28.5, a CD40 stimulating antibody, and purification of RNA, conversion to cDNA, measurement of mRNA expression using RNAseq. 2) Removal of thyroid tissues from CD40 over-expressing transgenic mice and wild type mice, purification of RNA, conversion to cDNA measurement of mRNA expression using RNAseq.
2012-10-03 | E-GEOD-39081 | biostudies-arrayexpress
Project description:Graves’ ophthalmopathy (GO) is an extrathyroidal complication of Graves’ hyperthyroidism. Orbital fibroblast, an important cell in the pathogenesis of GO, is responsible for GO characteristics during active and inactive stages; however, information on the extensive profiles and the mechanistic regulations behind orbital fibroblast phenotypes are currently limited. The aim of this study was to compare the proteome profile of orbital fibroblasts isolated from inactive GO, active GO and healthy control. The proteome profile was further integrated with global DNA methylation data to identify this epigenetics regulation involved in the pathogenesis of GO. Methods Orbital fibroblasts culture isolated from five inactive GO, four active GO and five controls were cultured for total protein and DNA extraction. The labelled and fractionated proteins were analyzed with a liquid chromatography tandem-mass spectrometer (LC-MS/MS). On the other hand, the bisulphite-treated DNA was measured with the Illumina Infinium Human Methylation 450K beadchip. Proteome and methylation data were validated by real-time quantitative (RQ)-PCR. Network, pathway and functional analysis were performed by Ingenuity (Qiagen). Results Orbital fibroblasts from active GO displayed overexpression of proteins typically involved with inflammation, cellular proliferation, hyaluronan synthesis and adipogenesis, while several proteins linked to extracellular matrix (ECM) biology and fibrotic disease were overexpressed in orbital fibroblasts from inactive GO. The DNA methylation patterns were similar in healthy control and inactive GO orbital fibroblasts which were distinct from active GO orbital fibroblasts. In orbital fibroblasts from active GO hypermethylated genes link to inflammation while those genes hypomethylated are involved in adipogenesis and autoimmune-related genes. For the network analysis, overlapped between hypermethylated and hypomethylated genes were observed including NF-B, ERK1/2, Alp, RNA polymerase II, Akt and IFNα. In addition, NF-κB, Akt and IFNα were also identified in networks from the differentially expressed proteins. In general, poor correlation between protein expression, DNA methylation and mRNA expression in our study was observed.
2021-01-27 | PXD022257 | Pride
Project description:Feline hyperthyroidism (FHT) is a debilitating disease affecting >10% of elderly cats. It is generally characterised by chronic elevation of thyroid hormone in the absence of circulating TSH. Understanding of the molecular pathogenesis of FHT is currently limited. However, FHT shares clinical and histopathological similarities with human toxic multinodular goitre, which has been associated with activating mutations in TSH receptor (TSHR) and Gsα encoding genes. Using RNA-seq transcriptomic analysis of thyroid tissue from hyperthyroid and euthyroid cats, we identified differentially expressed genes and dysregulated pathways in FHT, many of which are downstream of TSHR. In addition, we detected missense variants in thyroid RNA-seq reads that alter the structure of both TSHR and Gsα. All FHT-associated mutations were absent in germline sequence from paired blood samples. Only a small number of hyperthyroid cats demonstrated TSHR variation, however all thyroids from advanced cases of FHT carried at least one missense variant affecting Gsα. The activating nature of the acquired Gsα mutations was demonstrated by increased cAMP production in vitro. These data indicate that constitutive activation of signalling downstream of TSHR is central to the TSH-independent production of thyroid hormone in FHT, offering a novel therapeutic target pathway in this common disease.
2024-09-07 | GSE276271 | GEO
Project description:Medullary thyroid cancer (MTC) accounts for less than 5% of all thyroid cancers, and it is a rare neuroendocrine tumor which derives from calcitonin-secreting thyroid C cells.Given the underlying mechanism involved in MTC remain unclear, the development and the specific pathways of MTC require further investigation.here we employed the application of TMT6plex-based LC-MS/MS to identify and analyze the novel differentially-expressed proteins(DEPs) from MTC patients, To our best knowledge, it is the first study to comprehensively investigate the molecular mechanisms of MTC by proteomics technology from Chinese MTC patients’ tissues, and these DEPs identified in our study will provide a better understanding of the underlying pathophysiology of MTC, as well as may provide potential therapeutic targets for patients with MTC.
2020-05-26 | PXD005898 | Pride
Project description:Diagnosis of inflamed human orbit tissue with standard clinical and histopathology evaluation data is imprecise. A large number of these patients are diagnosed with the catch-all classification of nonspecific orbital inflammation (NSOI). We utilized gene expression analysis of orbit biopsies to assist in the classification of sarcoidosis, granulomatosis with polyangiitis (GPA), thyroid eye disease (TED), IgG4-associated disease, and subdivisions of NSOI. As part of this process, we are investigating correlations between gene expression levels and disease characteristics.
2015-06-06 | GSE58331 | GEO
Project description:Diagnosis of inflamed human lacrimal gland with standard clinical and histopathology evaluation data is imprecise. A large number of these patients are diagnosed with the catch-all classification of nonspecific orbital inflammation (NSOI). We utilized gene expression analysis of lacrimal gland biospy/surgical waste tissues to assist in the classification of sarcoidosis, granulomatosis with polyangiitis (GPA), thyroid eye disease (TED), and subdivisions of NSOI. As part of this process, we are investigating correlations between gene expression levels and disease characteristics.
2017-10-20 | GSE105149 | GEO