Somatic mutation in Primary Sjögren's Syndrome

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Autoimmune diseases affect 5% of the population and cause a wide range of painful disabilities that affect quality of life and may lead to life-threatening complications and early death. The most common autoimmune diseases in order of prevalence are rheumatoid arthritis, primary Sjögren's syndrome (PSS) and SLE or 'lupus'. In all these conditions, the immune system becomes hyperactive and damages tissues of the body including the joints, skin, mucous membranes, glands and vital organs. In health, immune responses are closely regulated so that auto-immunity dose not occur. Although research has identified many new ways to suppress auto-immunity, the 'aetiology' or fundamental reason that the immune system escapes control, is completely unknown.Through this research we are testing a new hypothesis that could explain why immune responses escape control in autoimmune disease. Throughout life, tissues of the body accumulate genetic mutations due to random errors in copying the DNA when cells divide. These mutations are known as 'somatic' mutations to indicate that they occur within an individual's lifetime and are not inherited from one generation to the next. Somatic mutations are the cause of cancer and may play an important role in many chronic and age-related diseases. Our research aims to test whether somatic mutations also cause autoimmunity. The idea is that genes that control immune responses may become defective so that immune cells escape from normal regulatory signals. There is evidence to support this idea from rare patients who are born with mutations that develop autoimmunity at a young age. We also know that patients with autoimmunity, especially those with PSS, are at risk of developing lymphoma and that some patients with lymphoma-related diseases get autoimmune problems. Our hypothesis suggests that somatic mutation is the factor linking both autoimmunity and lymphomaThe evidence we are looking for is whether patients with PSS have somatic DNA mutations in the immune cells that are causing their disease. Patients with PSS suffer dryness and severe irritation because their tear glands, salivary glands and other glands are attacked by immune cells. They are invited to join a UK Register and to allow their tissue biopsies to be used for research. We will use the latest tissue dissection methods to purify small populations of immune cells from the salivary glands of PSS patients and then ultra-sensitive DNA sequencing to detect somatic mutations in the DNA of the cells. If we find mutations, we will then determine which particular cell or cells of the immune system have the mutations and what problems the mutations cause in order to understand exactly how a mutation leads to the disease.This research promises to change our understanding of autoimmunity. If the hypothesis is correct then we anticipate that DNA mutation testing will become a new way to diagnose autoimmune disease, to predict how serious the condition will be and to monitor treatment. It will also provide specific information that will enable drugs to be targeted to individual somatic mutations. Ultimately this will improve the treatment of patients with autoimmune disease, enhancing their health and economic welfare and reducing the burden of autoimmune disease upon society.