Molecular determinants of immune tolerance in Graves' disease

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Autoimmune thyroid diseases are the most prevalent of the autoimmune conditions, with Graves' disease (GD) affecting close to 2% of women over a lifetime and impacting 7.5 million worldwide. In GD, the immune system generates antibodies that stimulate the thyroid gland leading to excessive thyroid hormone production (hyperthyroidism). Excess thyroid hormone affects multiple systems within the body including the heart, circulation, nervous system, skin and metabolic regulation, causing diverse symptoms such as elevated heart rate, irritability, sweating and weight loss. Thyroid eye disease, a complication of GD, also causes facial disfigurement with protuberance of the eyes, double vision and occasionally loss of vision. The current treatment for GD has remained largely unchanged since 1951, when the antithyroid drug carbimazole was introduced. Following a 6 month or longer course of carbimazole tablets about 50% of people will have a durable remission of their condition, whereas the other 50% will relapse, which is the rule in younger people. Relapsing patients may ultimately require radio-iodine treatment or surgical intervention to remove the thyroid gland, both leading to lifelong dependence on thyroid hormone replacement, with attendant monitoring costs.Graves' disease runs strongly in families and 80% of the risk has been shown to be owing to genetic factors. In addition, the exact cause of the thyroid overactivity is known: antibodies that mimic the shape of thyroid stimulating hormone (TSH) which persistently stimulate the TSH-receptor. Given the central role of these anti-TSH receptor antibodies (TRAbs) in causing GD, we need to understand more about why these antibodies are produced by the antibody-producing arm of the immune system (also known as the humoral immune system). Bone marrow-derived B lymphocytes, and their derivative cell types, plasmablasts and plasma cells are responsible for making these TRAb antibodies. My fellowship aims to understand what is different about the humoral immune system in GD patients who sustain a prolonged remission with disappearance of TRAbs following antithyroid drugs, compared to those whose TRAbs persist and who immediately relapse following the same medication.The study will involve a group of 120 adult GD patients who are about to stop taking the usual antithyroid drug therapy. I will compare many factors between the half who will remain cured of their thyroid disease (remission group) and those whose thyroid overactivity is about to come back (relapse group). Firstly, several blood markers of B lymphocyte production rate and development will be measured, including TRAbs, circulating B cell growth factors (eg. BAFF) and small DNA loops known as KRECs which indicate the rate of B lymphocyte production. Then the quantity of different gene-products in purified B cells from each group will also be examined using the powerful technique of RNA-sequencing. This will allow me to identify a B cell molecular fingerprint that distinguishes people entering disease remission vs those headed for relapse. Lastly, we will look at the genetic variations underlying these differences in gene expression and use this to confirm an inherited (genomic) underpinning for the relapse or remission phenomena. This will provide a catalogue of molecular differences (both RNA and genomic) in B cells between people with sustained remission and those who relapsed, along with functional information about their humoral immune response. This will give novel insights into how the immune system is able to become tolerant again following an autoimmune disease, which will help to advance the development of new treatments. Understanding the factors that determine the response to therapy will also give prognostic information and allow treatment to be tailored to the individual. Many other autoimmune diseases have a relapsing and remitting course, so this work may have widespread relevance.