Graves’ orbitopathy (GO), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves’ disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. The treatment of GO remains unsatisfactory and the majority of patients report long-term impairment of quality of life. To improve the outcomes of people with GO and thus reduce long-term illness and cost to society, research is needed to address the identification of risk factors, develop a better understanding of the pathophysiology of the disease, devise approaches for early diagnosis during the pre-clinical stage of the disease, and create novel and safe interventions. INDIGO will refine and optimise animal and in vitro models of Graves’ disease and GO, which are urgently required to facilitate the study of the pathogenesis of GO. INDIGO will address the identification of risk factors for the initiation and perpetuation of autoimmunity that causes disease, using the latest generation technologies to study variations in the microbiome in Graves and GO patients and controls. The effects of gut derived antigens, from micro-organisms and nutrients, on the autoimmune response will be tested in the animal model by probiotic and “contra-biotic” intervention. State of the art technology will be used to search for biomarkers that will identify patients that will progress to GO, during the preclinical phase of the disease when intervention is most likely to be successful. The successful completion of the project will be ensured by a partnership involving 2 SMEs, 3 academic institutions and the European Group on Graves’ Orbitopathy, each contributing complementary expertise and technology, the project will involve 5 secondments and 3 recruitments that will facilitate the exchange of knowledge and training.
The thyroid produces 2 hormones, thyroxine (T4) and tri-iodothyronine (T3) which regulate gene expression in many cells and control metabolic rate. In the euthyroid condition there is a perfect balance of T4/T3 levels which is controlled by negative feedback by T4/T3 on the pituitary and hypothallamus which secrete thyroid stimulating hormone (TSH) and TSH releasing hormone (TRH) respectively. TSH signals mainly via cAMP to regulate production of thyroid hormones and thyroid growth.
People with Graves’ disease (GD) secrete too much T4 and T3 because their immune system is dysregulated resulting in the production of autoantibodies to the TSH receptor (TSHR). The autoantibodies are called thyroid stimulating antibodies (TSAB) and they signal in the same way as TSH leading to hyperthyroidism (excess T4/T3, these provide negative feedback and suppress TSH levels) and formation of a diffuse goitre.
The hyperthyroidism which affects people with Graves’ disease (GD) increases basal metabolic rate and leads to many symptoms including heat intolerance, anxiety, increased heart rate and weight loss. GD patients may also experience problems with their eyes, a condition called Graves’ orbitopathy (GO, please see next slide) and also pretibial myxoedema in which the skin and underlying tissues on the shin become inflammed, itchy and discoloured and with the appearance of orange peel.
In people with Graves’ orbitopathy (GO, also known as thyroid eye disease or thyroid associated ophthalmopathy) the contents of the orbit expand by two main mechanisms; overproduction of extracellular matrix (ECM) and excess adipogenesis (formation of new fat cells from precursor ‘stem cells’). The tissue behind the eye provides protection but when its volume increases, since the orbit is a fixed bony structure, the eye itself has nowhere to go and is pushed forwards, a process known as proptosis or exophthalmos. In recent years progress has been made in understanding the mechanisms leading to orbital expansion and identifying a possible role for thyroid stimulating antibodies (TSAB) both in ECM production and adipogenesis. Much less is known about the changes in the immune system which lead to the loss of tolerance allowing generation and persistence of TSAB.