The role of clonal haematopoiesis in immune-mediated inflammatory diseases

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This project aims to understand more about a what causes a group of diseases known as immune-mediated inflammatory disease, abbreviated as IMID. These include allergic conditions like asthma and eczema, autoimmune disorders such as rheumatoid arthritis, colitis and lupus and inflammatory conditions like psoriasis. All IMID are characterised by an overactive immune system causing damage to organs. Although much is known about these diseases, it is less clear why the immune system becomes activated in the first place. About half of the risk of developing an IMID is determined by inherited genetic factors that control immune responses. It is also known that diet, smoking and other environmental factors can contribute. We are interested in a third possibility, that DNA mutations occurring at random can increase the risk of developing an overactive immune system. All cells of the body have copies of our DNA that gradually mutate as we age. This is known as somatic mutation because it is seen only in the tissues of the body and does not get inherited through generations. Mostly these mutations are silent but a small proportion give cells a growth advantage that allows them to expand into a small clone with abnormal properties. We can see that the white blood cells that form the immune system develop these small clones in some people. It is possible that these blood-derived clones activate the immune system and contribute to inflammatory diseases. We are therefore looking in the DNA of people with IMID for evidence that they have an increase in clonal haematopoiesis (blood-derived clones) compared with people who do not have IMID. In the first part of the project we will examine a large cohort of patients with inflammatory bowel disease and healthy controls and look for evidence of that patients with disease have more clonal haematopoiesis in their DNA. In the second part of the project, we examine a smaller cohort of patients with rheumatoid arthritis who have been followed closely to see if they respond to treatment and if they remain well when treatment stops. In these cases, we can ask if the presence of clonal haematopoiesis is able to predict what will happen to them. Specifically, we want to find out if clonal haematopoiesis is an adverse factor that identifies patients who are less likely to respond to treatment or more likely to have a flare up once treatment is stopped. Both approaches will help us to define if clonal haematopoiesis contributes to IMID and inform ways to exploit this information in the future to improve personalised medicine and potentially develop new approaches to therapy.