The role of clonal haematopoiesis in immune-mediated inflammatory diseases

这个项目旨在更多地了解是什么导致了一组被称为免疫介导的炎症性疾病，简称IMID。这些疾病包括哮喘和湿疹等过敏性疾病，类风湿关节炎、结肠炎和狼疮等自身免疫性疾病，以及牛皮癣等炎症性疾病。所有IMID的特征都是免疫系统过度活跃，导致器官受损。虽然我们对这些疾病了解很多，但免疫系统被激活的原因尚不清楚。患IMID的风险约有一半是由控制免疫反应的遗传因素决定的。众所周知，饮食、吸烟和其他环境因素也会造成这种情况。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DNA的副本，随着我们年龄的增长，这些DNA会逐渐发生突变。这被称为体细胞突变，因为它只出现在身体的组织中，不会世代遗传。这些突变大多是沉默的，但有一小部分使细胞具有生长优势，使它们能够扩展成具有异常特性的小型克隆。我们可以看到形成免疫系统的白细胞在一些人身上产生了这些小的克隆体。有可能是这些血液衍生的克隆激活了免疫系统，导致了炎症性疾病。因此，我们正在从患有IMID的人的DNA中寻找证据，以证明与没有患有IMID的人相比，他们的克隆造血能力（血液衍生克隆）有所增加。在该项目的第一部分，我们将检查一大批患有炎症性肠病的患者和健康对照者，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关节炎患者队列，他们被密切跟踪，看看他们是否对治疗有反应，以及治疗停止后他们是否保持良好。在这些情况下，我们可以询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，我们想要找出克隆造血是否是一个不利因素，确定患者不太可能对治疗有反应，或更有可能在治疗停止后突然发作。这两种方法都将帮助我们确定克隆造血是否有助于IMID，并告知如何在未来利用这些信息来改善个性化医疗，并有可能开发新的治疗方法。

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.