Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 13 (IL-13) has been demonstrated to have a crucial role in animal models of allergy and asthma. In human case-control genetic-association studies, the Arg130Gln polymorphism has been associated with elevated total serum IgE and an asthma diagnosis in atopic and nonatopic individuals (Graves et al. [2000] J. Allergy Clin. Immunol. 105:506-513; Heinzmann et al. [2000] Hum. Mol. Genet. 9:549-559). To apply family-based association methods, we obtained DNA samples from 685 asthmatic children from 640 sibships and their parents in the Childhood Asthma Management Program (CAMP). Six hundred and sixty-six asthmatic children had complete phenotypic information and were used for this analysis. We performed quantitative association analysis using the transmission disequilibrium test (TDT) on 22 individual phenotypes and 5 grouped phenotypes relating to allergy, airway responsiveness, pulmonary function, bronchodilator responsiveness, and asthma severity, using genotypes at the Arg130Gln polymorphism of the IL-13 gene. A positive association was obtained between Arg130Gln and a grouped phenotype of allergy (consisting of the individual phenotypes of eosinophils, IgE, and positive skin tests), using FBAT-GEE, a multivariate extension of the family-based association test (Lange et al. [2002] Biostatistics 1:1-15). The three phenotypes were then evaluated individually and revealed a significant association between total eosinophil count and the Arg130Gln locus; there was a trend for association between total IgE and the Arg130Gln polymorphism. The Arg130Gln polymorphism is associated with an elevated eosinophil count as well as with a grouped allergy phenotype, in children with mild to moderate asthma. No evidence for association was found between Arg130Gln and airway responsiveness, asthma diagnosis, or asthma severity.
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PMID:Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program. 1243 2

The aim of this study was to evaluate thyroid peroxidase (TPO) mRNA expression in peripheral blood of patients with benign and malignant thyroid disease. Included were 120 thyroid cancer patients, 85 patients with goitre or Graves' disease (GD) and 54 healthy volunteers. TPO mRNA expression was analysed in peripheral blood by nested RT-PCR. In cancer patients, RT-PCR results were compared with staging, grading and serum thyroglobulin (TG) measurement. TPO transcripts were detected in 7/10 (70%) patients with known metastases of thyroid cancer and in 39 of 110 (36%) patients without metastases (P<0.05), in 15/44 (34%) patients with goitre, in 17/41 (41%) cases with GD and in 4/54 (7.4%) subjects in the control group (P<0.05, controls vs all patients with thyroid disease). Among cancer patients without metastatic disease, RT-PCR results correlated positively with lymph node status (P=0.05), grading (P=0.01) and elevated serum thyroglobulin levels (P=0.03). This is the largest study investigating the use of the TPO-RT-PCR assay. Positivity in TPO-RT-PCR correlates significantly with metastatic disease in cancer patients and with the presence of thyroid disease in general. To date, TPO-RT-PCR cannot substitute for standard techniques in the diagnosis of local recurrence or metastatic spread in thyroid cancer patients. However, as results of TPO-RT-PCR correlate significantly with lymph node status, grading and serum TG measurements in patients with non-metastatic disease, TPO seems to be an interesting molecular marker to look at in follow-up studies.
J Mol Endocrinol 2002 Dec
PMID:Detection of thyroid peroxidase mRNA in peripheral blood of patients with malignant and benign thyroid diseases. 1245 31

Individualised dosage models are frequently applied for radioiodine therapy in patients with Graves' hyperthyroidism, especially in Europe. In these dosage schemes the thyroid volume is an important parameter. Thyroid volume determinations are usually made with ultrasonography or with thyroid scintigraphy, although the accuracy of planar scintigraphy for this purpose is not well established. The aim of this study was to compare the accuracy of three modalities for the determination of the thyroid volume in patients with Graves' disease: planar scintigraphy (PS), single-photon emission tomography (SPET) and ultrasonography (US). These three modalities were compared with magnetic resonance imaging (MRI) as the gold standard. Thyroid volume estimations were performed in 25 patients with Graves' disease. The PS images were subjected to filtering and thresholding, and a standard surface formula was used to calculate the thyroid volume. With SPET the iteratively reconstructed thyroid images were filtered, and after applying a threshold method an automatic segmentation algorithm was used for the volume determinations. Thyroid volumes were estimated from the US images using the ellipsoid volume model for multiple two-dimensional measurements. For MRI, thyroid segmentation was performed manually in gadolinium-enhanced T1-weighted images and a summation-of-areas technique was used for the volume measurements. The thyroid volumes calculated with MRI were 25.0+/-13.8 ml (mean+/-SD, range 7.0-56.3 ml). PS correlated poorly with MRI ( R(2)=0.61) and suffered from a considerable bias (-4.0+/-17.6 ml). The differences between PS and MRI volume estimations had a very large spread (33+/-58%). For SPET both the correlation with MRI ( R(2)=0.84) and the bias (1.8+/-11.9 ml) were better than for PS. US had by far the best correlation with MRI ( R(2)=0.97) and the best precision, but the bias (6.8+/-7.5 ml) was not negligible. In conclusion, SPET is preferred over PS for accurate measurements of thyroid volume. US is the most accurate of the three modalities, if a correction is made for bias.
Eur J Nucl Med Mol Imaging 2003 Apr
PMID:Comparison of methods for thyroid volume estimation in patients with Graves' disease. 1254 Nov 36

The thyrotrophin receptor (TSHR) provides an autoantigenic link between the thyroid and orbit in Graves' (GD) and thyroid eye diseases (TED). We measured TSHR transcripts in different fat depots to determine whether TSHR expression levels are influenced by the autoimmune/inflammatory process and/or thyroid hormone status, using quantitative real-time PCR. Nine intact or fractionated adipose samples, from patients with GD and/or TED, were analysed ex vivo. Eight expressed the TSHR, at levels approaching the thyroid, and one was at the limit of detection. Thirteen/fifteen orbital and abdominal fat samples from patients free of GD and TED, measured ex vivo, were negative for TSHR transcripts and two were at the limit of detection. All preadipocyte samples induced to differentiate in vitro expressed the TSHR. To investigate the influence of thyroid hormone status on adipose TSHR expression, we induced hyper- and hypothyroidism in BALBc mice by administering tri-iodothyronine and propylthiouracil respectively. In euthyroid animals, whole fat samples were at the limit of detection and were not altered by thyroid hormone status. The results show that adipose TSHR expression ex vivo indicates adipogenesis in progress in vivo and is associated with the autoimmune/inflammatory process in GD and TED but is not restricted to the orbit or influenced by thyroid hormone status.
J Mol Endocrinol 2003 Jun
PMID:Adipose thyrotrophin receptor expression is elevated in Graves' and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. 1279 Aug 6

Autoimmune thyroid disease (AITD) occurs in two common forms: Graves' disease and Hashimoto thyroiditis. On the basis of functional and experimental data, it has been suggested that the gene encoding cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a candidate gene for conferring susceptibility to thyroid autoimmunity. In this review, we critically evaluate the evidence for pathogenetic involvement of CTLA-4 in the various forms of AITD and focus on the possible role of genetic variation of the CTLA4 locus. Population genetics data strongly suggest a role for the CTLA4 region in susceptibility to AITD. However, further functional studies are required to understand the significance of CTLA4 polymorphisms in the pathogenic mechanism of AITD.
J Mol Endocrinol 2003 Aug
PMID:CTLA-4 and its role in autoimmune thyroid disease. 1291 22

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves' disease, type 1 insulin-dependent diabetes mellitus and Addison's disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.
Expert Rev Mol Med 2001 Jul 23
PMID:Immunological pathomechanisms in vitiligo. 1458 44

Purification of TSH receptor autoantibodies (TRAb) from the serum of patients with Graves' disease (GD) might help to elucidate the nature of these disease causing autoantibodies. We describe here for the first time the successful affinity purification of human TRAb. Affinity purification was performed in a four step procedure with human recombinant TSH receptor (TSH-R) expressed in K562 cells. Purification from six different serum pools from patients with GD and two individual sera (one with only thyroid stimulating antibodies (TSAb) one with only thyroid blocking antibodies (TBAb)) resulted in a purity of 39.2+/-3.8 IU/mg TRAb or 25.7+/-2.1 microg IgG/IU (about 3.5-13.7 microg TRAb/ml serum). The average enrichment based on the respective original serum was 3420-fold (range 1200-10,000). The kDa of the purified TRAb were in the range of 0.7-2.6 x 10(-10)M. All purified TRAb (except from the TBAb serum which showed blocking activity) showed a more than 1000-fold stronger stimulation in the TSAb bioassay based on the IgG content than the original serum, and similar stimulation based on international units (IU/l) TRAb. When labelled purified TRAb were used in a competitive assay as tracer instead of bovine TSH, their binding to the human recombinant TSH-R on tubes was displaced by 99 of 100 GD sera (selected for TBII activity). Correlation to the standard TSH tracer was r=0.92. Interestingly, the use of TRAb tracer derived from a patient with TSAb and a patient with TBAb gave virtually identical results (r=0.93) with these patients, suggesting similar if not identical binding sites for both TRAb subtypes. In conclusion, this is the first report on the purification of human TRAb from the serum of patients with GD. The purified TRAb are of low concentration with high affinity, strong TBII and TSAb activity. Further characterisation may allow new insights in TRAb epitope localisation, the pathology of GD and the differences between TSAb and TBAb. Also, their use as tracer in a competitive assay is the first report on a completely homogenous assay with high sensitivity for TSH-R autoantibodies.
Mol Cell Endocrinol 2003 Dec 30
PMID:Affinity purification and diagnostic use of TSH receptor autoantibodies from human serum. 1465 52

The thyroid-stimulating hormone (TSH, or thyrotropin) receptor (TSHR) mediates the activating action of TSH to the thyroid gland, resulting in the growth and proliferation of thyrocytes and thyroid hormone production. In Graves' disease, thyroid-stimulating autoantibodies can mimic TSH action and stimulate thyroid cells. This leads to hyperthyroidism and abnormal overproduction of thyroid hormone. TSHR-antibodies-binding epitopes on the receptor molecule are well studied. Mechanism of TSHR-autoantibodies production is more or less clear but a susceptibility gene, which is linked to their production, is still unknown. Genetic studies show no linkage between the TSHR gene and Graves' disease. Among three common polymorphisms in the TSHR gene, only the D727E germline polymorphism in the cytoplasmic tail of the receptor showed an association with the disease, and this association is weak. The absence of a strong genetic effect of the TSHR polymorphisms in such a common and complex disorder as Graves' disease may be explained by a high degree of evolutionary conservation in TSHR. This can be shown by naturally existing germline and somatic mutations in the TSHR gene that cause various types of nonautoimmune and hereditary thyroid disease.
Mol Genet Metab 2003 Dec
PMID:Thyroid-stimulating hormone receptor and its role in Graves' disease. 1465 50

Graves' thyroid tissue has been shown to express elevated levels of human sodium/iodide symporter (hNIS) mRNA and protein. In the present work, we demonstrate for the first time that hNIS gene expression in Graves' disease (GD) is up-regulated by Graves' IgG. Here, in transient transfection experiments using FRTL-5 cells, hNIS promoter and enhancer/luciferase construct showed an up to six-fold increase in transcriptional activity after incubation with purified Graves' IgG. Mutation of a CRE site in hNIS enhancer inhibited Graves' IgG response. In addition, mutation of a novel putative regulatory region in hNIS promoter reduced the stimulation three-fold. This discovered putative regulatory sequence might play a role in hNIS up-regulation by Graves' IgG and TSH. The data presented here complement our current knowledge of the pathogenesis of GD and will contribute to a better understanding of mechanisms regulating the thyroid iodide concentrating activity.
Mol Cell Endocrinol 2003 Dec 31
PMID:Graves' IgG activate upstream enhancer of the sodium/iodide symporter. 1506 79

Quinone oxidoreductase 2 (QR2) purified from human red blood cells was recently shown to be a potential target of the quinoline antimalarial compounds [Graves et al., (2002) Mol. Pharmacol. 62, 1364]. QR2 catalyzes the two-electron reduction of menadione via the oxidation of N-alkylated or N-ribosylated nicotinamides. To investigate the mechanism and consequences of inhibition of QR2 by the quinolines further, we have used steady-state and transient-state kinetics to define the mechanism of QR2. Importantly, we have shown that QR2 when isolated from an overproducing strain of E. coli is kinetically equivalent to the enzyme from the native human red blood cell source. We observe ping-pong kinetics consistent with one substrate/inhibitor binding site that shows selectivity for the oxidation state of the FAD cofactor, suggesting that selective inhibition of the liver versus red blood cell forms of malaria may be possible. The reductant N-methyldihydronicotinamide and the inhibitor primaquine bind exclusively to the oxidized enzyme. In contrast, the inhibitors quinacrine and chloroquine bind exclusively to the reduced enzyme. The quinone substrate menadione, on the other hand, binds nonspecifically to both forms of the enzyme. Single-turnover kinetics of the reductive half-reaction are chemically and kinetically competent and confirm the inhibitor selectivity seen in the steady-state experiments. Our studies shed light on the possible in vivo potency of the quinolines and provide a foundation for future studies aimed at creating more potent QR2 inhibitors and at understanding the physiological significance of QR2.
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PMID:Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines. 1507


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