Dissecting the mechanisms of immune-mediated inflammation: a systems-immunology approach

更好地了解免疫介导炎症性疾病（IMIDs）中影响免疫反应和诱导炎症的早期机制将有助于制定更好的治疗、预防和早期诊断策略。到目前为止，研究主要集中在已经受到特定IMIDs影响的患者身上，有时是在疾病的后期阶段。因此，关于IMIDs常见的早期机制的重要见解可能被忽略了。我们假设这些早期机制是由参与健康受试者正常炎症免疫调节的相同机制失调引起的。因此，我们建议a)确定未受影响个体炎症免疫调节的主要参与者，b)使用受特定和多种IMIDs影响的大量患者样本验证其在IMIDs中的作用。我们已经很好地描述了来自TwinsUK队列的2000对双胞胎的免疫血细胞，其中274对受IMID影响。我们收集了长达9年的随访数据，包括大量临床和生化变量，包括可以量化潜在炎症状态的变量。后续信息确定了另外130对双胞胎在收集后患上了该病。这个具有良好特征的样本还包括172对同卵双胞胎，其中只有一人已经或已经受到影响，是研究免疫和炎症之间关系的理想样本。当前研究的另一个限制是免疫学研究往往集中在对单个成分的独立分析上。这种方法没有考虑到免疫系统的真正复杂性，它的功能依赖于多个免疫细胞的协同作用。我们将使用计算模型来分析免疫细胞及其相互作用，并确定与炎症相关的免疫细胞群。为了增加我们研究的力量，我们将进一步表征一些化合物，这些化合物是免疫细胞之间和免疫细胞之间沟通的关键介质。我们之前已经证明免疫细胞的丰度是由基因控制的。我们将使用遗传学作为一种工具来区分这些免疫细胞群中哪些是炎症状态的结果，哪些是炎症状态的原因-增加IMID风险。事实上，如果一组遗传变化影响了一组免疫细胞的组成，而这些变化引起炎症并增加了IMID的风险，那么同样的一组遗传变化可能在患有IMID的受试者中更频繁。为了调查这一点，我们将使用来自UKBiobank的50万人的现有基因数据，其中包括5万名IMIDs患者。在确定TwinsUK中控制不同组炎症相关免疫细胞的遗传变化后，我们将使用UKBiobank样本来测试它们对IMID的影响，并优先考虑它们在增加IMID风险中的重要性。最后，在TwinsUK中，我们已经描述了肠道细菌群落的组成和功能。我们的肠道拥有数万亿微生物，它们与免疫系统相互作用。我们将研究肠道细菌与imid相关的优先免疫细胞组之间的相互作用，以鉴定可能成为修饰免疫细胞组成的潜在目标的细菌。总之，通过利用现有数据和先进的统计模型，该项目将查明不同IMIDs共有的免疫介导炎症的新机制，并将进一步探索微生物组与相关免疫细胞之间的相互作用。这些结果将构成使用特定疾病队列进行进一步调查的基础，并确定和验证潜在的治疗靶点，这些靶点将通过介入性研究得到验证。

A better understanding of the early mechanisms that affect the immune response and induce inflammation in immune mediated inflammatory diseases (IMIDs) would help in developing better strategies for their treatment, prevention, and early diagnosis. Until now, research has mainly focused on patients already affected by specific IMIDs, and sometimes at later stages of the disease. Thus, important insights on the common early mechanisms of IMIDs may have been missed. We hypothesize that these early mechanisms are caused by a dysregulation of the same mechanisms that are involved in the normal immune regulation of inflammation in healthy subjects. Consequently, we propose to a) identify the main players involved in the immune regulation of inflammation in unaffected individuals, and b) verify their role in IMIDs using a very large sample of patients affected by specific and multiple IMIDs. We have already finely characterised the immune blood cells of 2,000 twins from the TwinsUK cohort, of which 274 are affected by IMID. We have collected up to 9 years of follow up data, with a large number of clinical and biochemical variables, including variables that allow quantification of the underlying inflammation state. Follow up information has identified an additional 130 twins that developed the disease after collection. This well-characterised sample, which also includes 172 identical twins of whom only one of them was already or become affected, is ideal to investigate the relationship between immunity and inflammation.A further limitation of current research is that immunological studies are often focused on the independent analysis of individual components. This approach does not take into account the real complexity of the immune system, whose function relies on the concerted action of multiple immune cells. We will use computational models to analyse altogether the immune cells and their interactions and to identify groups of immune cells associated with inflammation. To increase the power of our study, we will further characterise a number of chemical compounds that are key mediators of the communication with and between immune cells. We have previously shown that the abundance of immune cells is controlled by genes. We will use genetics as an instrument to distinguish which of these groups of immune cells is a consequence of the inflammation state, and which are a cause of it - increasing IMID risk. Indeed, if a set of genetic changes affects the composition of a group of immune cells, and these cause inflammation and increases IMID risk, then the same set of genetic changes are likely to be more frequent in subjects who have developed IMID. To investigate this, we will use already available genetic data in 500,000 people from the UKBiobank, which includes 50,000 IMIDs patients. After identifying the genetic changes controlling the different groups of inflammation-associated immune cells in TwinsUK, we will use the UKBiobank sample to test their effect on IMID, and to prioritise their importance in increasing IMID risk.Finally, in TwinsUK, we have already characterised both composition and function of the gut bacterial community. Our gut hosts trillions of microbes, which mutually interact with the immune system. We will investigate the interplay between the gut bacteria and the prioritised sets of IMID-associated immune cells, to identify bacteria that could be potentially targeted to modify immune cell composition.In summary, by taking advantage of already available data and advanced statistical modelling, this project will pinpoint novel mechanisms of immune-mediated inflammation shared by different IMIDs, and will further explore the interplay between the microbiome and the involved immune cells. These results will constitute the basis for further investigations using disease-specific cohorts and to identify and validate potential therapeutic targets, that will be validated through interventional studies.