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Rebecca S Bahn - One of the best experts on this subject based on the ideXlab platform.
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forkhead transcription factor foxo1 is regulated by both a stimulatory Thyrotropin Receptor Antibody and insulin like growth factor 1 in orbital fibroblasts from patients with graves ophthalmopathy
Thyroid, 2015Co-Authors: Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Rebecca S BahnAbstract:Background: Activation of Thyrotropin Receptor (TSHR) and/or insulin-like growth factor (IGF-1) Receptor (IGF-1R) enhances HA production and adipogenesis in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) and recapitulates the tissue remodeling characteristic of the orbit in GO. A functional relationship between TSHR and IGF-1R has long been postulated, and recently bidirectional crosstalk between the Receptors in GO fibroblasts was demonstrated. Because the transcription factor Forkhead box O-1 (FOXO1) was recently shown to be a critical downstream mediator of TSH and IGF-1 effects on thyrocyte proliferation, studies were designed to determine whether FOXO1 might similarly act as a common mediator of M22, a stimulatory TSHR Antibody (TSAb), and IGF-1 in GO orbital fibroblasts. Methods: FOXO1 mRNA and protein were measured in orbital tissue specimens derived from normal individuals and patients with GO. In addition, the control of FOXO1 cellular localization was investigated using quant...
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a small molecule antagonist inhibits Thyrotropin Receptor Antibody induced orbital fibroblast functions involved in the pathogenesis of graves ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Susanne Neumann, Marvin C Gershengorn, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the Thyrotropin Receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
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a stimulatory Thyrotropin Receptor Antibody enhances hyaluronic acid synthesis in graves orbital fibroblasts inhibition by an igf i Receptor blocking Antibody
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Seema Kumar, Seethalakshmi Iyer, Hilary Bauer, Michael J Coenen, Rebecca S BahnAbstract:Context: Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH Receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. Objective: The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I Receptor (IGF-IR)-blocking Antibody (1H7) or inhibitors of various downstream signaling cascades. Design: GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. Main Outcome Measures: HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. Results: M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P <...
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a stimulatory Thyrotropin Receptor Antibody m22 and Thyrotropin increase interleukin 6 expression and secretion in graves orbital preadipocyte fibroblasts
Thyroid, 2010Co-Authors: Seema Kumar, Michael J Coenen, Reagan Schiefer, Rebecca S BahnAbstract:Background: Patients with Graves' ophthalmopathy (GO) have circulating autoantibodies directed against the Thyrotropin Receptor (TSHR) and elevated levels of the proinflammatory cytokine interleuki...
Yoshinori Iwatani - One of the best experts on this subject based on the ideXlab platform.
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involvement of functional polymorphisms in the tnfa gene in the pathogenesis of autoimmune thyroid diseases and production of anti Thyrotropin Receptor Antibody
Clinical and Experimental Immunology, 2009Co-Authors: Naoya Inoue, Mikio Watanabe, Takashi Nanba, Masamitsu Wada, Takashi Akamizu, Yoshinori IwataniAbstract:The severity of Hashimoto's disease (HD) and intractability of Graves' disease (GD) varies among patients. Severity of HD is associated with the functional +874A/T polymorphism for interferon-γ, an inflammatory cytokine. To clarify the association between functional polymorphisms in two other inflammatory cytokine genes [tumour necrosis factor (TNF)-α and interleukin (IL)-2] and the severity of autoimmune thyroid disease (AITD), we examined the TNF-α−1031T/C, TNF-α−857C/T and IL-2 −330T/G polymorphisms in genomic DNA samples. We genotyped 41 patients with intractable GD, 34 patients with GD in remission, 41 patients with severe HD, 36 patients with mild HD and 70 healthy controls. The frequency of carriers of TNF-α−1031C (CT + CC), which correlates with higher TNF-α production, was significantly higher in HD and GD patients than in controls, but was not associated with the severity of HD. In GD patients, the levels of anti-Thyrotropin Receptor Antibody (TRAb) at onset of the disease was higher in patients with the TNF-α−857T (CT + TT) genotype, which correlates with higher TNF-α production, than in those with the −857CC genotype. We found no differences in the IL-2 −330T/G polymorphism among groups of AITD patients. In conclusion, the functional −1031T/C polymorphism of the TNFA gene is associated with the development of AITD and the functional −857C/T polymorphism is associated with the levels of TRAb in active GD patients.
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increase in immunoglobulin g3 secreting cells in intractable graves disease
Thyroid, 2003Co-Authors: Yumi Nakamoto, Makoto Niki, Mikio Watanabe, Yoshinori IwataniAbstract:Isotype switching of immunoglobulin (Ig)-secreting cells is regulated by a set of cytokines. In the present study, we studied the relation between the number of peripheral blood mononuclear cells spontaneously secreting IgG, IgM, IgA, and their subclasses and the disease severities in autoimmune thyroid diseases. Ig-secreting cells were measured by enzyme-linked immunospot (ELISPOT) assay in 99 euthyroid patients with Graves' disease (GD) or Hashimoto's disease (HD) and 13 normal subjects. The number of IgG3-secreting cells was significantly higher in patients with intractable GD who had been undergoing treatment with antithyroid drugs for more than 5 years but who did not go into remission than in patients with GD in remission. This number correlated significantly with the serum level of Thyrotropin Receptor Antibody (TRAb) in all patients with GD. These data suggest that the number of IgG3-secreting cells whose isotype switching is stimulated by interleukin (IL)-10 and IL-4 may be related to the disease...
Seema Kumar - One of the best experts on this subject based on the ideXlab platform.
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forkhead transcription factor foxo1 is regulated by both a stimulatory Thyrotropin Receptor Antibody and insulin like growth factor 1 in orbital fibroblasts from patients with graves ophthalmopathy
Thyroid, 2015Co-Authors: Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Rebecca S BahnAbstract:Background: Activation of Thyrotropin Receptor (TSHR) and/or insulin-like growth factor (IGF-1) Receptor (IGF-1R) enhances HA production and adipogenesis in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) and recapitulates the tissue remodeling characteristic of the orbit in GO. A functional relationship between TSHR and IGF-1R has long been postulated, and recently bidirectional crosstalk between the Receptors in GO fibroblasts was demonstrated. Because the transcription factor Forkhead box O-1 (FOXO1) was recently shown to be a critical downstream mediator of TSH and IGF-1 effects on thyrocyte proliferation, studies were designed to determine whether FOXO1 might similarly act as a common mediator of M22, a stimulatory TSHR Antibody (TSAb), and IGF-1 in GO orbital fibroblasts. Methods: FOXO1 mRNA and protein were measured in orbital tissue specimens derived from normal individuals and patients with GO. In addition, the control of FOXO1 cellular localization was investigated using quant...
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a small molecule antagonist inhibits Thyrotropin Receptor Antibody induced orbital fibroblast functions involved in the pathogenesis of graves ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Susanne Neumann, Marvin C Gershengorn, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the Thyrotropin Receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
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a stimulatory Thyrotropin Receptor Antibody enhances hyaluronic acid synthesis in graves orbital fibroblasts inhibition by an igf i Receptor blocking Antibody
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Seema Kumar, Seethalakshmi Iyer, Hilary Bauer, Michael J Coenen, Rebecca S BahnAbstract:Context: Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH Receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. Objective: The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I Receptor (IGF-IR)-blocking Antibody (1H7) or inhibitors of various downstream signaling cascades. Design: GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. Main Outcome Measures: HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. Results: M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P <...
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a stimulatory Thyrotropin Receptor Antibody m22 and Thyrotropin increase interleukin 6 expression and secretion in graves orbital preadipocyte fibroblasts
Thyroid, 2010Co-Authors: Seema Kumar, Michael J Coenen, Reagan Schiefer, Rebecca S BahnAbstract:Background: Patients with Graves' ophthalmopathy (GO) have circulating autoantibodies directed against the Thyrotropin Receptor (TSHR) and elevated levels of the proinflammatory cytokine interleuki...
C T Choo - One of the best experts on this subject based on the ideXlab platform.
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graves ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels prevalence natural history and Thyrotropin Receptor Antibody levels
Thyroid, 2000Co-Authors: D H C Khoo, Suchin Ho, N G Morgenthaler, Layleng Seah, K S Fong, S P Chee, C T Choo, S E AwAbstract:The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, ...
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graves ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels prevalence natural history and Thyrotropin Receptor Antibody levels
Thyroid, 2000Co-Authors: D H C Khoo, N G Morgenthaler, Layleng Seah, K S Fong, S P Chee, P H K Eng, E S Tai, C T ChooAbstract:The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, (b) measure the prevalence of Thyrotropin Receptor antibodies (TRAb) in these cases, and (c) identify possible predictors of hyperthyroidism. Over a 30-month period, 1020 cases of thyroid eye disease were evaluated, of which only 19 (1.9%) met the diagnostic criteria. Ten (1%) had subclinical thyrotoxicosis, 7 (0.7%) were euthyroid, and 2 (0.2%) were hypothyroid as determined by a third-generation Thyrotropin (TSH) assay. TRAb levels were measured in 16 of these 19 patients. The prevalence of TRAb varied according to the assay used. Polyethylene glycol-extracted thyroid-stimulating immunoglobulin (PEG-TSI), unfractionated thyroid-stimulating immunoglobulin (uTSI), first-generation porcine TSH-binding inhibitory immunoglobulin (pTBII), and second-generation human TSH-binding inhibitory immunoglobulin (hTBII) assays were positive in 93.8%, 50%, 18.8%, and 81.3% of patients, respectively. TRAb was detected by at least one method in all patients. Patients were followed up for 15 to 45 months. Hyperthyroidism developed in 4 patients (25%). Suppressed TSH levels and elevated TBII were predictors of hyperthyroidism. When sensitive assays are used, the prevalence of GO patients without elevated thyroid hormone levels is extremely low. The sensitivities of assays for TRAb detection differ substantially in these cases. PEG extraction improves the detection rate of TSI (p = 0.02), and hTBII assays improve the detection of TBII in these patients (p = 0.002). The high prevalence of TRAb in such cases supports a role for these antibodies in the pathogenesis of thyroid-associated eye disease.
Michael J Coenen - One of the best experts on this subject based on the ideXlab platform.
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forkhead transcription factor foxo1 is regulated by both a stimulatory Thyrotropin Receptor Antibody and insulin like growth factor 1 in orbital fibroblasts from patients with graves ophthalmopathy
Thyroid, 2015Co-Authors: Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Rebecca S BahnAbstract:Background: Activation of Thyrotropin Receptor (TSHR) and/or insulin-like growth factor (IGF-1) Receptor (IGF-1R) enhances HA production and adipogenesis in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) and recapitulates the tissue remodeling characteristic of the orbit in GO. A functional relationship between TSHR and IGF-1R has long been postulated, and recently bidirectional crosstalk between the Receptors in GO fibroblasts was demonstrated. Because the transcription factor Forkhead box O-1 (FOXO1) was recently shown to be a critical downstream mediator of TSH and IGF-1 effects on thyrocyte proliferation, studies were designed to determine whether FOXO1 might similarly act as a common mediator of M22, a stimulatory TSHR Antibody (TSAb), and IGF-1 in GO orbital fibroblasts. Methods: FOXO1 mRNA and protein were measured in orbital tissue specimens derived from normal individuals and patients with GO. In addition, the control of FOXO1 cellular localization was investigated using quant...
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a small molecule antagonist inhibits Thyrotropin Receptor Antibody induced orbital fibroblast functions involved in the pathogenesis of graves ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Seema Kumar, Seethalakshmi Iyer, Michael J Coenen, Susanne Neumann, Marvin C Gershengorn, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the Thyrotropin Receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
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a stimulatory Thyrotropin Receptor Antibody enhances hyaluronic acid synthesis in graves orbital fibroblasts inhibition by an igf i Receptor blocking Antibody
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Seema Kumar, Seethalakshmi Iyer, Hilary Bauer, Michael J Coenen, Rebecca S BahnAbstract:Context: Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH Receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. Objective: The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I Receptor (IGF-IR)-blocking Antibody (1H7) or inhibitors of various downstream signaling cascades. Design: GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. Main Outcome Measures: HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. Results: M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P <...
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a stimulatory Thyrotropin Receptor Antibody m22 and Thyrotropin increase interleukin 6 expression and secretion in graves orbital preadipocyte fibroblasts
Thyroid, 2010Co-Authors: Seema Kumar, Michael J Coenen, Reagan Schiefer, Rebecca S BahnAbstract:Background: Patients with Graves' ophthalmopathy (GO) have circulating autoantibodies directed against the Thyrotropin Receptor (TSHR) and elevated levels of the proinflammatory cytokine interleuki...