Mechanisms of altered T cell epigenetics in lupus

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PROJECT SUMMARY Lupus lead is an autoimmune disease in which environmental effects acting within a permissive genetic background to immune dysregulation.Dysfunction of multiple cell types is associated with production of anti-nuclear autoantibodies (ANA), generation of immune complexes, and tissue damage. Genome wide association studies have identified >100 susceptibility loci that contribute to disease; however, the cellular mechanisms through which these polymorphisms lead to cellular dysfunction are unknown. Accumulating evidence suggests that genetic susceptibility to lupus is mediated via cell-specific epigenetic changes altering transcriptional profiles. Inpreliminary experiments, we identified alupus-specific epigenetic and transcriptional signature in naïve and effector CD4+ T cells. We find that: 1) the epigenetic and segregates and identified susceptibility, milieu cells; enriched together, immunologic landscape of naive activated CD4+ T cells i s significantly different in patients with lupus as compared with healthy donors and by disease; 2) A significant number of OCRs of CD4+ T cells in lupus are present in naïve T cells precede T cell activation; 3) The lupus-specific OCRs disproportionately align with susceptibility alleles in GWAS analyses of lupus . Epigenetic hanges could be cell-intrinsic, secondary to genetic and precede clinical presentation or cell-extrinsic and induced by the abnormal immunologic of lupus Intrinsic pathways are suggested by the presence of a disease-specific pathway in naïve T extrinsic effects of inflammation are suggested by analyses showing t hat the lupus-specific signature is in NF-kB-dependent DNA-binding motifs downstream of signaling via TNF family members. Taken our data lead us to hypothesize that genetic predisposition to l upus cooperates with the lupus environment to alter the epigenome of hematopoietic cells prior to activation. c . First, we will probe the hypothesis that the open epigenetic landscape that characterizes lupus is cell intrinsic and precedes disease. We will define the minimal hematopoietic lupus signature by characterizing the epigenome of resting B cells and monocytes. We will perform a cross sectional analysis of patients and their healthy first degree relatives to define the lupus-specific epigenetic modules that precede disease. Secondly, we will define the effect of TNF family members on the epigenetic landscape by manipulating cytokines in in vitro assays. We will then examine CD4 + T cells in patients treated with TNF blockade to directly define a TNF-dependent epigenetic signature. Finally, we have utilized bioinformatic approaches to generate disease-specific enrichment scores for multiple pathways, including TNF-dependent signaling and the Type I interferon pathway. With this information, we will determine the relationship between clinical disease and epigenetic changes at a level of detail that has not been previously possible. Our findings will lead to basic insights into genetic and epigenetic regulation of gene expression, and point to novel potential targets for therapeutic intervention to treat and/or prevent lupus.