The proteolysis of immunoglobulin G with long-acting thyroid-stimulating activity.
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ABSTRACT:
SUBMITTER: Dorrington KJ
PROVIDER: S-EPMC1264928 | biostudies-other | 1966 Mar
REPOSITORIES: biostudies-other
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Project description:Highly purified bovine TSH (thyroid-stimulating hormone) was labelled with 125I by using very low concentrations of chloramine-T. Human thyroid membranes prepared by discontinuous sucrose-density-gradient centrifugation were homogeneous on examination by electron microscopy. Incubation of radioiodinated TSH with the membranes showed that radioactivity could be bound to the membranes. Under the experimental conditions described here, binding was dependent on time and temperature and was a saturable phenomenon. Preincubation of the membranes with unlabelled hormone inhibited the subsequent binding of 125I-labelled TSH. Similarly, inhibition by the long-acting thyroid stimulator also showed a saturation behaviour. A rapid and sensitive method for the detection of the long-acting thyroid stimulator is described.
| S-EPMC1165191 | biostudies-other
Project description:ObjectivesThe clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the longitudinal association between changes in serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb) levels and course of disease activity and severity over time.DesignThis was a multicentre, prospective, observational study.SettingFifteen tertiary care oculoplastic service centres in Korea.ParticipantsSeventy-six patients with newly diagnosed TED were included and followed up for 12 months.MethodsWe evaluated clinical characteristics and serum TRAb levels at baseline, 6 and 12 months of TED diagnosis. Additionally, we analysed longitudinal associations between the serum TRAb levels and clinical activity score (CAS), no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, sight loss (NOSPECS) score and proptosis.ResultsThyroid-stimulating immunoglobulin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) levels decreased during the 1-year follow-up, whereas disease activity measured using CAS decreased mainly in the first 6 months. Disease severity measured using NOSPECS score and proptosis remained unchanged. Moreover, inter-person differences in TBII levels were associated with CAS, NOSPECS score and proptosis over time, whereas inter-person differences in TSI levels were associated with NOSPECS score. Subgroup analysis of patients with a baseline CAS≥4 demonstrated that within-person changes in TSI levels affected the CAS and NOSPECS score.ConclusionsFollow-up measurement of serum TSI and TBII levels may help evaluate TED prognosis and enable accurate clinical decision-making.
| S-EPMC9214404 | biostudies-literature
Project description:BackgroundThe bioassay of thyroid-stimulating immunoglobulin was reported to have a similar performance to the commonly used thyroid-stimulating hormone binding inhibition assay, also known as thyroid receptor antibody assay. The normal reference range of thyroid receptor antibody levels indicates the withdrawal of anti-thyroid drugs in the recent clinical guidelines.MethodsA prospective, longitudinal observational study was conducted to evaluate the prognostic value of thyroid-stimulating immunoglobulin in patients with Graves' disease.ResultsA total of 77 patients with Graves' disease treated with anti-thyroid drugs were in a continuous follow-up until 1 year after anti-thyroid drugs discontinuation. Commercial kits of thyroid-stimulating immunoglobulin and M22-thyroid-stimulating hormone binding inhibition assay were used and compared. Thyroid-stimulating immunoglobulin was all negative in healthy controls, Hashimoto thyroiditis, and subacute thyroiditis. Thyroid-stimulating immunoglobulin value was highest in untreated patients with Graves' disease (p < 0.001). Under anti-thyroid drugs treatment, thyroid-stimulating immunoglobulin value decreased gradually. A total of 21 patients had positive thyroid-stimulating immunoglobulin at the end of treatment. According to clinical fate of patients with Graves' disease after withdrawal of anti-thyroid drugs, thyroid-stimulating immunoglobulin value and positivity in patients with relapse were significantly higher than that reported in patients with remission (p = 0.001, p < 0.001). After adjustment for age, gender, initial thyroid receptor antibody, initial thyroid-stimulating immunoglobulin, and thyroid receptor antibody at the end of treatment, the odds ratio of positive thyroid-stimulating immunoglobulin for the risk of relapse was 33.271 (95% confidence interval: 4.741-233.458, p < 0.001) and odds ratio of quantitative thyroid-stimulating immunoglobulin was 1.009 (95% confidence interval: 1.002-1.015, p < 0.001).ConclusionThyroid-stimulating immunoglobulin is a good predictor of relapse in patients with Graves' disease treated with anti-thyroid drugs. It might be safer to discontinue anti-thyroid drugs when thyroid-stimulating immunoglobulin and thyroid receptor antibody were both negative.
| S-EPMC8481717 | biostudies-literature
Project description:Graves' hyperthyroidism is an autoimmune disease occurring spontaneously in humans and caused by autoantibodies that stimulate the thyrotropin receptor. In mice, inducing Graves'-like hyperthyroidism requires in vivo expression of the thyrotropin receptor using plasmid or adenovirus vectors. However, mice with different genetic backgrounds vary markedly in their susceptibility to induced hyperthyroidism. Further, in some strains major disparities exist between the induction of hyperthyroidism and detection of thyroid-stimulating antibodies. To break tolerance, virtually all Graves' mouse models involve immunization with human thyrotropin-receptor DNA and the standard thyroid-stimulating antibody bioassay uses cells expressing the human thyrotropin receptor. We hypothesized, and now report, that disparities between hyperthyroidism and thyroid-stimulating antibody bioactivity are explained, at least in part, by differential antibody recognition of the human vs the mouse thyrotropin receptor. The genetic basis for these species differences was explored using genotyped, recombinant-inbred mouse strains. We report that loci in the immunoglobulin heavy chain variable region as well as in the major histocompatibility complex region contribute in a strain-specific manner to the development of antibodies specific for the human or the mouse thyrotropin receptor. The novel finding of a role for immunoglobulin heavy chain variable region gene involvement in thyroid-stimulating antibody epitopic specificity provides potential insight into genetic susceptibility in human Graves' disease.
| S-EPMC4108286 | biostudies-literature
Project description:OBJECTIVE:To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN:Retrospective cohort study. SETTING:The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS:Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE:TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES:Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS:162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS:In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.
| S-EPMC6719286 | biostudies-other
Project description:BACKGROUND:Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE:The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN:We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS:Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ?2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION:Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.
| S-EPMC5712235 | biostudies-literature
Project description:Production of thyroid-stimulating hormone receptor (TSHR) antibodies represents the hallmark of Graves' disease (GD) pathogenesis. Thus, for more than two decades the TSHR gene has been at the center of studies intended to elucidate its contribution to disease pathology. The advent of genome-wide association technology allowed to establish a strong association of the TSHR gene with GD. Subsequent fine-mapping studies narrowed the disease-susceptibility region to a 40?kb sequence in intron 1, where at least five GD-associated SNPs in tight linkage disequilibrium were identified. The current challenge is to understand the functional mechanisms by which these polymorphisms modify physiological processes and trigger disease. The aim of this review is to summarize the current knowledge on the role of the TSHR gene in GD pathogenesis, which has been gained through linkage and association studies, as well as to discuss the emerging mechanisms underlying biological implications of TSHR variants in the development of GD.
| S-EPMC5376554 | biostudies-literature
Project description:Human thyroid stimulating hormone (TSH) is a glycoprotein secreted by the anterior part of the pituitary gland. TSH plays an important physiological role in the regulation of hypothalamic-pituitary-thyroid axis by modulating the release of the thyroid hormones from the thyroid gland. It induces iodine uptake by the thyroid, promotes thyroid epithelial differentiation and growth, and protects thyroid cells from apoptosis. Impairment of TSH signal transduction pathway leads to thyroid disorders such as goitre, hypothyroidism and hyperthyroidism, which can have complex clinical manifestations. TSH signaling is largely effected through two separate pathways, the adenylate cyclase and the phospholipase C pathways. In spite of its biomedical importance, a concise signaling map of TSH pathway is not available in the public domain. Therefore, we have generated a detailed signaling map of TSH pathway by systematically cataloging the molecular reactions induced by TSH including protein-protein interactions, post-translational modifications, protein translocation events and activation/inhibition reactions. We have cataloged 40 molecular association events, 42 enzyme-substrate reactions and 16 protein translocation events in TSH signaling pathway resource. Additionally, we have documented 208 genes, which are differentially regulated by TSH. We have provided the details of TSH pathway through NetPath (http://www.netpath.org), which is a publicly available resource for human signaling pathways developed by our group. We have also depicted the map of TSH signaling using NetSlim criteria (http://www.netpath.org/netslim/) and provided pathway maps in Wikipathways (http://www.wikipathways.org/). We anticipate that the availability of TSH pathway as a community resource will enhance further biomedical investigations into the function and effects of this important hormone.
| S-EPMC3830942 | biostudies-literature
Project description:BackgroundHypothyroidism has been known to be associated with hyperlipidemia, endothelial dysfunction and atherosclerosis. Elevation of thyroid-stimulation hormone (TSH) is a gold standard to detect these conditions. However, no large studies have investigated the association between TSH elevation and long-term clinical outcomes in patients with acute myocardial infarction (AMI).HypothesisHypothyroidism is associated with higher mortality in patients with AMI.MethodsA total of 4748 AMI patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents were consecutively enrolled. We analyzed 1977 patients whose thyroid function data available after the exclusion of hyperthyroidism and possible central hypothyroidism. Patients were divided into two groups; euthyroid group (n = 1846) with normal TSH and normal free thyroxine (FT4); hypothyroidism group (n = 131) with elevated TSH and normal or low FT4. The two groups were subsequently compared with their all-cause and cardiac mortalities.ResultsMedian follow-up duration was 3.5 years. Hypothyroidism group were older, included in more females, and had higher incidences of atrial fibrillation, stroke, and renal dysfunction. Elevated TSH was associated with significantly higher all-cause mortality (26.0% vs 11.7%, P < 0.0001) and cardiac mortality (9.2% vs 4.6%, P = 0.014). The multivariate Cox proportional hazards model identified that TSH elevation was a significant predictor of all-cause mortality (adjusted hazard ratio 1.560, 95% confidence interval 1.017 to 2.392, P = 0.041).ConclusionsOur data suggest that AMI patients with TSH elevation had worse clinical outcome. Moreover, TSH elevation was a predictor of all-cause mortality in patients with AMI.
| S-EPMC6489767 | biostudies-literature
Project description:1. Digestion of rabbit immunoglobulin M (IgM) by papain for 5h, in the absence of reducing agent, gives Fabmu and Fc(5)mu fragments in high yield. Shorter periods give fragment Fc(5)mu with one or more Fabmu fragments still attached. 2. Reducing agent in the absence of a denaturant cleaves rabbit IgM into half-subunits, each containing one mu chain and one light chain. Digestion by papain in the presence of such a reducing agent destroys the Fcmu domains.
| S-EPMC1168411 | biostudies-other