The role of clonal haematopoiesis in immune-mediated inflammatory diseases

该项目旨在更多地了解是什么导致了一组称为免疫介导的炎症性疾病（简称IMID）的疾病。这些包括过敏性疾病如哮喘和湿疹，自身免疫性疾病如类风湿性关节炎，结肠炎和狼疮以及炎症性疾病如牛皮癣。所有IMID的特征是免疫系统过度活跃，导致器官损伤。虽然对这些疾病了解很多，但尚不清楚为什么免疫系统首先被激活。大约一半的IMID风险由控制免疫反应的遗传因素决定。众所周知，饮食、吸烟和其他环境因素也会起作用。我们对第三种可能性感兴趣，即随机发生的DNA突变会增加免疫系统过度活跃的风险。身体的所有细胞都有我们的DNA副本，随着年龄的增长而逐渐突变。这被称为体细胞突变，因为它只出现在身体的组织中，不会遗传给后代。大多数情况下，这些突变是沉默的，但一小部分给细胞的生长优势，使他们能够扩大到一个小的克隆与异常属性。我们可以看到，形成免疫系统的白色血细胞在某些人身上形成了这些小克隆。这些血液来源的克隆可能会激活免疫系统并导致炎症性疾病。因此，我们正在IMID患者的DNA中寻找证据，证明与没有IMID的人相比，他们的克隆造血（血液来源的克隆）增加。在该项目的第一部分，我们将检查一个大型炎症性肠病患者和健康对照组，并寻找疾病患者DNA中有更多克隆造血的证据。在该项目的第二部分，我们检查了一个较小的类风湿性关节炎患者队列，这些患者被密切跟踪，看看他们是否对治疗有反应，以及当治疗停止时他们是否保持良好。在这些情况下，我们可以问克隆造血的存在是否能够预测他们会发生什么。具体来说，我们想知道克隆性造血是否是一个不利因素，可以确定哪些患者不太可能对治疗有反应，或者一旦治疗停止，更有可能出现突发事件。这两种方法都将帮助我们确定克隆造血是否有助于IMID，并为未来利用这些信息来改善个性化医疗和潜在开发新的治疗方法提供信息。

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.