Unravelling the pathogenic mechanisms in Graves’ orbitopathy
Alan Chun Hong Lee, George J. Kahaly
Abstract
Graves' orbitopathy (GO) is characterized by orbital inflammatory infiltration, expansion of orbital tissues due to de novo adipogenesis and over-production of hydrophilic glycosaminoglycans, as well as myofibroblastic differentiation resulting in tissue fibrosis. Thyrotropin receptor antibody (TSH-R-Ab) is the major stimulus, which activates thyrotropin receptor (TSH-R)/insulin-like growth factor-1 receptor (IGF-1R) and its downstream signalling in orbital fibroblasts (OF). Clinical evaluation of TSH-R-Ab, the specific biomarker of Graves' disease (GD) and the associated orbitopathy, provides important clinical information concerning diagnosis, disease monitoring and prognosis of GO. TSH-R/IGF-1R crosstalk represents the principal mechanism of activation of OF, the key effector cells in GO. T cells and monocytes/macrophages predominate in the inflammatory infiltrates and B-T cell co-stimulation results in mutual activation. Mast cell-derived products also activate OF. In the presence of various pro-inflammatory molecules, activated OF and lymphocytes perpetuate orbital inflammation and mediate tissue remodelling. Enhanced oxidative stress drives various pathological processes in GO and many antioxidant agents have shown inhibitory effects on OF. Highly differential gene and protein expression exists between GO and normal subjects, as well as between active/severe and inactive/mild GO, providing important insights into the disease mechanisms. The lack of confirmed genetic susceptibility to GO development suggests that epigenetic mechanisms (e.g. DNA methylation and microRNAs) may play a role in regulating gene and protein expression, and hence disease phenotypes. The gut microbiome differs significantly between GO patients and healthy individuals. Modifying gut microbiota in GO animal models improves GO. Emerging evidence indicates that hypercholesterolaemia is associated with increased risk of developing GO, while statin use is a protective factor.