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

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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.