Investigation of candidate biomarkers in Graves' disease and thyroid-associated ophthalmopathy

摘要

Thyroid-Associated Ophthalmopathy (TAO) is a debilitating inflammatory condition of the orbit occurring in 30-50% of Graves' Disease (GD) patients. It is not currently possible to predict which GD patients will develop TAO or the severity of their eventual ophthalmic manifestations. The aim of this thesis was to evaluate novel biomarkers for this purpose.ududI developed two immunoassays to detect serum antibodies to insulin-like growth factor-1 receptor (IGF-lR-Ab) in GD, TAO and healthy controls (HC). Assays were validated to measure commercial monoclonal IGF-lR-Ab but no study group differences, or correlation with clinical activity or severity, were noted with sera.ududDifferential IGF-lR expression on peripheral blood CD4+ and CDS+ T lymphocyte memory subsets was observed, although without variance between groups. However, T cell differentiation was perturbed, with elevated proportions of naïve, and reduced cytokine-producing effector memory T cells, in GD and TAO compared to HC.ududNuclear magnetic resonance-based serum metabolomic analysis differentiated GD and TAO subjects, and varying TAO clinical activity, with good uncorrected sensitivity and specificity. Distinguishing metabolites included lactate, isopropanol, methylguanidine and pyruvate.ududCollectively these data cast doubt on a simple model of IGF-lR-Ab being responsible for orbital inflammation in GD, but highlight the biomarker potential of metabolomics in TAO.