Abstract
AbstractOrbital fibroblasts (OF) expressing functional TSH receptors (TSHR) have been recognized as the target cells of the autoimmune attack in Graves’ orbitopathy (GO). Immunocompetent cells infiltrate the orbit, and present antigens (TSHR) to T-cells. Activated T-cells, cytokines and TSHR antibodies bind to OF, and induce secretion of excessive amounts of hydrophylic glycosaminoglycans (like hyaluronan) and differentiation of a subset of OF into mature fat cells (adipogenesis). The subsequent increase of extraocular muscle and orbital fat volume explain in a mechanistic way the symptoms and signs of GO. Genetic immunization of experimental animals with TSHR A-subunit (but not with IGF-1Rα) plasmid generates a fair mouse model of GO. Simultaneous activation of TSHR and IGF-1R potentiates the HA response induced by TSHR antibodies, but IGF-1R stimulating antibodies are absent and TSHR-stimulating antibodies do not recognize the IGF-1R. Crosstalk between TSHR and IGF-1R might occur by binding arrestin-β-1, which could act as a scaffold bringing both receptors closer together. One TSHR signaling pathway might be independent from the IGF-1R, whereas another TSHR pathway interacts downstream with the IGF-1R signaling pathway. Susceptibility genes for Graves’ hyperthyroidism are the same as for GO. Smoking is a preventable risk factor for GO. Recent data suggest hypercholesterolaemia also carries a risk.
Publisher
Springer International Publishing
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