Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY: Imbalance of immune and inflammatory activity is a hallmark of immune-mediated dis- eases. Genome-wide association studies have identified hundreds of loci that increase susceptibility to immune- mediated diseases. Functional effects of these genetic variants are difficult to infer as they might only impact a particular cell type and their effects may be restricted to specific points in development. Studies on adult immune cells have shed light on mediator cells and mechanisms of disease-associated variants, however, childhood is a critical yet understudied stage in the development of the immune system. Genetic determinants of T cell develop- ment and effector function during childhood have not been studied and their role in immune-mediated diseases is unknown. We propose to fill gaps that link the genetics of immune-mediated diseases to their effector cells, developmen- tal stages, and mechanisms. Our goals are 1) to understand the importance of genetically mediated T cell development and central tolerance induction on immune-mediated diseases and 2) to identify the importance of childhood immune phenotypes on disease in adulthood. To reach these goals, we propose studying the dynamic genetic influences of human T cell development using single-cell gene expression quantitative trait mapping in human pediatric thymus samples. To study the genetics of the progression from development to peripheral effector function, we will collect peripheral immune cells from the same pediatric patients. Furthermore, we will study genetic effects on pediatric immune cells in different activation states to pinpoint genetic effects acting upon stimulation. To investigate genetic effects on immune cells at different ages, we will integrate the genetic effects we identify in pediatric immune cells with those derived from adult and neonatal cells from other studies. Lastly, we will examine genetic effects on central and peripheral immune phenotypes in the context of immune-mediated diseases. We will generate profiles of chromatin accessi- bility in thymus and peripheral immune cells to identify regulatory mechanisms in chromatin. This will allow us to conduct colocalization studies of immune-mediated disease variants, immune cell-associated variants and open chromatin regions. We will then estimate causality of immune phenotypes on immune-mediated diseases using a Mendelian Randomization framework. In summary, our research offers an innovative approach to study complex disease mechanisms: it combines quantitative genetics and immunology using clinical specimens to generate new insights into the genetics of immune-mediated diseases, their effector cells and molecular mechanisms. This mechanistic understanding of disease-associated variants is fundamental for advancing towards novel treatments of immune-mediated dis- eases.
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