Integrative omics to understand human immune variation

There are millions of different microorganisms that enter our bodies and interact with us on a cellular level daily. A proportion of these microbes are not friendly to us and can potentially become a threat by infecting our cells and using our bodies’ resources. Such infections can impair bodily functions, undermine our health and ultimately lead to death. In order to counteract these millions of potential threats, human bodies have evolved a series of mechanisms that are able to seek and destroy pathogens. We call these mechanisms our immune system. The immune system is a complex and highly interconnected network of organs, cells, circulating factors and proteins (cytokines). Together, these components are able to recognize pathogens and subsequently organize and execute a proper response, all this while recognizing its own cells and avoiding self-damage. Having protection against external threats is essential to multicellular life as it allows to have a controlled internal self-environment and lets us interact “safely” with an ever-changing environment. We can better appreciate the importance of the immune system when it becomes deregulated. For example, if our bodies are not able to respond quickly enough to dangerous pathogens, we can become susceptible to infectious diseases. On the other hand , if the response to pathogens is too quick or too strong, our own cells can be recognized as intruders and become targets of our own immune system giving rise to autoimmune diseases. We humans have slight differences in the way our immune system responds to pathogens. This inter-individual variation has been widely observed, even among completely healthy individuals. The variation in response is an essential component of our everlasting conflict with pathogens, as it ensures that at least a few of us will react just differently enough to survive pandemic-like scenarios. The source of this variation has not yet been fully understood, although we do know that it mainly arises from the interaction between our genetic information (the composition of our DNA), the environmental conditions we live in (lifestyle) and the triggers we encounter (certain microbes or molecules). In Section 1 of this thesis we explored the main drivers of the interindividual variation of the human immune system in the Dutch population. We did so by ascertaining the impact of common genetic variation, host status and the environment on the immune composition and response with the use of deeply phenotyped population-based cohorts. Some of the leading protagonists of the immune system are the specialized immune cells that are in circulation in our blood. These cells are constantly being restocked and bombarded with environmental signals that tell them in which location of our body they are needed. In Chapter 2, we characterized the main sources of variation in the circulating levels of 34 independent immune cells found in blood. We observed that these cells have very different sources of variation. For example, we found that the number of B cells, the cells that seek and recognize dangerous pathogens, are mostly driven by environmental queues. While the levels of T cells, which are the cells responsible for destroying any recognized threats, are mostly driven by our genetics. Another way to look at the variation within the immune system is through the production of signaling proteins (cytokines) by an immune cell once they come in contact with a pathogen. In Chapter 3, we conducted a study aimed to characterize the genetic component behind cytokine production upon pathogen stimulation in the general population. We found that our genetics is the biggest source of variation, and that genetic variants (specific letters, in specific positions in our DNA) are located near genes (sections of our DNA) that encode the proteins that recognize dangerous microorganisms. Being able to predict how much of these signaling proteins are produced once we come in contact with a pathogen is key to bring personalized medicine to the clinical practice of infectious and immune mediated diseases. In Chapter 4, we explored the possibility of predicting the immune response by integrating as many layers of biological information as possible. These biological layers included measurements of microbiome composition (the “good” microbes in our gut), levels of circulating metabolites, and genetics. We were able to fairly accurately predict the response to pathogens of certain proteins, even if we only used genetics. There’s still plenty of room for improvement before we are able to predict a patient’s immune status, but newer, cheaper and more precise ways to measure immune components are being developed at the moment, which could help us bring personalized medicine into infectious and immune mediated diseases. In Section 1 of this thesis, we showed how important host genetics and environmental queues are for the immune system. The interaction between our genome and our environment happens through the exchange of information. This information flows from the environment into our cells in the form of signaling molecules, these subsequently activate certain genes (special regions of our DNA) to be copied into RNA at certain rates (in a process known as transcription). The RNA is then translated (translation as in our cells reads from nucleotides to amino acids) into proteins, which are the acting molecules of our cells. The global quantification of RNA (all the copied DNA present in a cell) is known as transcriptome, and is widely used to infer the biological processes that are being carried out in our cells. In Section 2 of this thesis we aimed to characterize the role of the transcriptome in immune cells. First, in Chapter 5, we developed a novel computational approach to study the impact of common genetic variation in the transcriptome in specialized immune cells. We were able to achieve this by predicting the proportion of multiple immune cells in circulation (using gene expression levels). We were then able to detect genes modulated by genetic variation in disease relevant immune cells by combining the predicted proportions with genetics and levels of gene expression. Understanding how our DNA modulates changes of gene expression in disease relevant cells can help us understand the development of diseases. We explored this type of strategy in Chapter 6, where we used as model, immune cells derived from gut biopsies. The job of these “gut immune cells” is to monitor and protect us against pathogens. Nevertheless, in the context of certain immune and inflammatory diseases, these cells can turn against us and start attacking our own cells. Hence, we explored the transcriptome response of gut derived T cells to immune signaling proteins. We found that these cells are very sensitive to signaling proteins that are specific to the gut tissue. Additionally, we observed that within these cells, the genes that are being deregulated are near genetic risk factors for immune mediated diseases of the gut. Understanding how specialized immune cells are affected by triggers can help us find novel therapeutic targets for immune mediated diseases