TERRY FRANCIS DAVIES

..However, it may also provide decoys for TSHR antibodies, thus influencing their biological action and clinical effects. This review discusses the role of the TSHR in the physiological and pathological stimulation of the thyroid...

..The gene for the TSHR on chromosome 14q31 has been implicated as coding for the major autoantigen in the autoimmune hyperthyroidism of Graves' disease (GD) to which T cells and autoantibodies are directed...

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..Transmission disequilibrium test (TDT) analysis also showed an association of Tgms2 with AITD (p = 0.02). We concluded therefore that the Tg gene was a major AITD susceptibility gene because it was both linked and associated with AITD...

..We propose that this aberrant process, whereby TSHR-Abs influence antigen processing, is a novel mechanism for the maintenance and exacerbation of autoimmune thyroid disease...

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..In view of the significant genetic heterogeneity observed in AITD, analyzing subsets is an efficient way to resolve heterogeneity and identify novel genes...

..Recently non-classical signaling elicited by neutral antibodies has also been described, raising the need for a new classification of TSHR-Abs...

..5 and 2.5 mU/L...

..In contrast, loss of function of a mutant TSHR (Pro --> Leu at 556) in congenital hypothyroid mice activates osteoclast differentiation, confirming once again our premise that TSHRs have a critical role in regulating bone remodeling...

..These studies define a role for TSH as a single molecular switch in the independent control of both bone formation and resorption...

..In addition, I- uptake activity was observed in these cells. Our results indicate that ES cells can be induced to differentiate into thyroid follicular cells, providing a powerful tool to study embryonic thyroid development and function...

..In conclusion, both the extrinsic and intrinsic actions of human CTLA-4 were not affected by the signal peptide A49G polymorphism. Therefore, the linkage of the CTLA-4 A49G SNP to AITD is most likely secondary to linkage disequilibrium...

..The aim of the present study was to investigate the role of HLA in AITD and to explain the observed associations, but lack of linkage, by examining only AITD families with the associated allele, DR3...

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..The data also indicated that the intrathyroidal cellular immunity in this model was not related to TSHR-Ab formation and was an independent reflection of the T-cell immune response to TSHR antigen...

..Here, we have examined the contribution of the ectodomain to constitutive multimerization of the TSHR and determined the possible residue(s) that may be involved in this interaction...

..Because downstream thyroid cell signaling by the TSHR is both ligand dependent and independent, this may explain why TSHR-Abs are able to have variable influences on thyroid cell biology...

..Activin A is clearly a major regulator of thyroid endoderm...

..Knowledge of the structure/function relationship of the TSHR is beginning to provide a greater understanding of thyroid physiology and thyroid autoimmunity...

..Potential therapeutic implications include the development of antagonists to circulating FSH and its osteoclastic receptor...

..TSH and its receptor could become valuable drug targets in treating bone loss...

..Thus, fetal male cells are valid candidates for modulating autoimmune thyroid disease in pregnancy and postpartum...

..Hence, the degree of intramolecular cleavage must also modulate TSHR signaling...

..This may help explain the inflammatory nature of this common disorder...

..Inhibition of these oligomeric forms by ligand binding returns the TSHR to an activated state...

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..The evidence that low TSH levels predispose to osteoporosis in hyperthyroidism is discussed in view of the emerging role of pituitary hormones in bone biology...

..Thus, inactivation of the TSHR by stimulating TSHR autoantibodies (TSHR-Ab's) in Graves disease patients may provide a functional explanation for the poor correlation between thyroid function and serum TSHR-Ab concentrations...

..Hence, TSHR-stimulating and blocking antibodies cannot be distinguished purely on the basis of their conformational epitope recognition...

..However, HLA-DR3 and CTLA-4 did not have a stronger effect in the familial GD patients, suggesting that additional genes must contribute to the aggregation of GD within families...

..It is hoped that in the near future additional AITD susceptibility genes will be identified and the mechanisms by which they induce AITD will be unraveled...

..We can now provide results that not thyroid hormones but also TSH itself has an equally important role to play in bone remodeling...

..The isolation and characterization of MS-1 provides a novel explanation for the prolonged thyroid stimulation in this disease which may be secondary to the lack of receptor cleavage in addition to the prolonged half-life of IgG itself...

..The loci that continue to show evidence for linkage in the expanded data set represent serious candidate regions for gene identification...

..The mechanism of this long-standing increased susceptibility requires further delineation...

..TSHR-Abs can be detected by competition assays of TSHR-Abs for labeled TSH, or monoclonal TSHR-Ab binding to solubilized TSHRs, or by bioassays using thyroid cells or mammalian cells expressing recombinant TSHRs...

..The results suggest that TNFalpha is the critical cytokine mediating the downstream antiresorptive effects of TSH on the skeleton...

..g., DR4) are phenotype specific; and that because the logarithm of odds score for T1D + HT was lower than for T1D alone, additional non-HLA loci must contribute to the shared genetic susceptibility to T1D and AITD...

..There were no significant associations between TSH level or thyroglobulin antibody positivity and the risk of moderately preterm delivery...

..The aim of this study was to determine the impact of pregnancy on Hashimoto's thyroiditis as revealed by changes in postpregnancy levothyroxine requirements...

..We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism...

..This model of bystander cell detection confirmed that such an effect occurs in EAT and adds weight to the importance of this phenomenon in the initiation of autoimmune thyroid disease...

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..Access to specific early-developing cell populations, such as the thyroid stem cells in the embryonic stem cell system, provides an experimental approach to characterizing key molecular events involved in thyrocyte commitment...

..Clinical guidelines have a very arbitrary recommendation of aspiration biopsy in all lesions greater than 1 cm in size, but this proposal has no scientific basis and should always be viewed in the clinical context...

..One such stimulating mAb has demonstrated a number of differences in its regulation of TSHR post-translational processing. These differences are likely to be reflective of TSHR-Abs seen in Graves' disease...

..Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT...

..To examine whether the insulin receptor (INSR) gene contributes to genetic susceptibility to the polycystic ovary syndrome (PCOS)...

..6%). Statistical analysis confirmed that XCI skewing was significantly associated with AITD (P = 0.004, OR = 4.0), demonstrating that the degree of XCI is an important contributor to the increased risk of females in developing AITD...

..053). Our results may suggest an interaction between the R- and CC variants in conferring susceptibility to GD. These results, if confirmed, may imply that these two variants interact biologically to increase the odds of GD...

..These results demonstrate the complexity in the generation of multiple autoimmune phenotypes in NOD mice and indicate that CCR7 is a key molecule in their development...

..The current review describes these molecular mechanisms in relation to the way thyroid hormones, and the pituitary hormone thyrotropin (TSH), regulate skeletal morphogenesis and remodeling...

..These studies will provide more definitive data on the linked and associated loci contributing to AITD. ..

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..for 4 pre-doctoral and 5 post-doctoral trainees who will be assigned to an experienced group of preceptors to provide training and research in fundamental cellular and molecular biological techniques in a wide choice of endocrine systems ..

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..The benefit to the individual and society is potentially great in alleviating suffering due to the more severe forms of this thyroid disorder, especially Graves'ophthalmopathy. ..

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