Function of asthma- and allergic disease-associated risk variants and genes in lung immune cells

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Asthma and allergic diseases (AADs) affect over 25 million children and adults in the United States, and AAD incidence has been increasing over the last 4 decades. There is significant clinical heterogeneity in AAD due to multiple overlapping but distinct underlying mechanisms of disease. Both innate and adaptive branches of the immune system play key roles in asthma pathogenesis and the heterogeneity of the disease. Yet, studies of immune cells in asthma have rely mostly on peripheral blood cells, which have different origins, composition, receptors and function than immune cells in the lung. Our work combined with those of others demonstrated that subsets of lung T cells, B cells, macrophages and dendritic cells have substantial differences from their counterparts in blood and other tissues. Thus, circulating immune cells are a poor model for tissue-based immune cells, and focus should shift toward lung-resident immune cells in studies of AADs. In Project 2, we focus on discovering mechanisms that guide the function of specific lung-resident immune cells and how genetic variation perturbs these mechanisms. The premise that most AAD-associated genetic variants impart their effects by changing the properties of cell type-specific regulatory elements thereby altering expression of target genes, implies that the phenotypic effects of these variants should be studied in homogenous populations of specific lung cells. Nevertheless, the largest public expression quantitative trait loci (eQTL) databases, such as GTEx, sample whole lung, which represents a mix of many different cell types. Nearly all that is known about genetic effects in immune cells are from studies of peripheral blood immune cells. As such, extrapolation of the effects of AAD risk variants from these resources are not likely to reflect their effects in AAD-relevant lung immune cells. Thus, our overall goal is to address these significant gaps by leveraging this collaborative program's unique resources to determine i) how specific lung immune cell types relevant to AADs contribute to immune responses, ii) the effects of genetic variation on these responses, iii) how different lung immune cell types coordinate to generate immune responses and how this is skewed by AAD-relevant inflammatory states, and iv) the functional effects on AAD causal variants and their target genes. We will achieve our goals through 3 Aims. Aim 1 will use human lymphoid and myeloid lung-resident immune cells to determine the landscape of stimulation-responsive genes, enhancers and stimulation-responsive chromatin and the effects of genetic variation on these responses. Aim 2 will determine how putative causal variants affect gene expression and downstream function in lung immune cells under asthma relevant conditions. Aim 3 will investigate the role of genetic variation identified through our omics studies on the in vivo response to allergic stimulation using CRISPR and BAC transgenic technology. Achieving our goals will link cells-specific mechanisms of immune regulation, genetic risk in AAD and specific genes, ultimately leading to treatments for asthma and allergic diseases.