Mechanisms of altered T cell epigenetics in lupus

狼疮 T 细胞表观遗传学改变的机制

• 批准号: 10536870
• 负责人: TERRI M. LAUFER
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-19 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536870
• 关键词: ATAC-seq; Affect; Age; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Bioinformatics; Biological; Biological Assay; Biology; Blood; CD4 Positive T Lymphocytes; Cells; Chromatin; Clinical; Cross-Sectional Studies; DNA; DNA Binding; Data; Diagnostic; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Family member; First Degree Relative; Functional disorder; Gene Expression Profile; Gene Expression Regulation; Generations; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomics; Helper-Inducer T-Lymphocyte; Hematopoietic; Heterogeneity; Hydroxychloroquine; Immune; Immunologics; In Vitro; Individual; Inflammation; Interferon Type I; Knowledge; Lead; Link; Lupus; Mediating; Molecular; Mycophenolic Acid; NF-kappa B; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Predisposition; Production; Proteomics; Research Personnel; Resources; Rest; Secondary to; Signal Transduction; Susceptibility Gene; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; TNF gene; Techniques; Therapeutic Intervention; Tissues; Twin Multiple Birth; cell type; clinical effect; cytokine; effector T cell; epigenetic regulation; epigenome; experimental study; genetic variant; genome wide association study; genome-wide analysis; in vitro Assay; insight; monocyte; novel; prevent; response; systemic inflammatory response; targeted treatment; transcriptome sequencing

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.

项目 概括 狼疮 带领 是一种自身免疫性疾病，其中环境影响在允许的遗传背景下起作用 免疫失调。多种细胞类型的功能障碍与抗核细胞的产生有关 自身抗体（ANA）、免疫复合物的产生和组织损伤。 研究已确定超过 100 个导致疾病的易感位点；然而，其细胞机制尚不清楚； 这些多态性如何导致细胞功能障碍尚不清楚。 表明对狼疮的遗传易感性是通过细胞特异性表观遗传变化介导的 在初步实验中，我们鉴定了 alupus 特异性的表观遗传和转录谱。 初始和效应 CD4+ T 细胞中的转录特征我们发现：1）表观遗传。 和 隔离 和 已鉴定 敏感性， 环境 细胞； 丰富的 一起， 免疫学 天真的风景 与健康捐献者相比，狼疮患者的活化 CD4+ T 细胞存在显着差异 2) 狼疮中大量的 CD4+ T 细胞 OCR 存在于幼稚 T 细胞中 先于 T 细胞激活；3) 狼疮特异性 OCR 与易感性等位基因不成比例地对齐 在狼疮的 GWAS 分析中，表观遗传变化可能是细胞固有的，继发于遗传。 并先于临床表现或细胞外源性并由异常免疫学诱导 狼疮的内在途径由幼稚 T 中疾病特异性途径的存在表明 分析显示，狼疮特异性特征是炎症的外在影响 NF-kB 依赖性 DNA 结合基序通过 TNF 家族成员进行信号传导下游。 我们的数据使我们确信狼疮的遗传易感性与狼疮相辅相成 在激活之前改变造血细胞表观基因组的环境。 c 。 首先，我们将探查 狼疮特征的开放表观遗传景观是细胞内在的并且先于细胞的假设 我们将通过表征静息的表观基因组来定义最小的造血系统狼疮特征。 我们将对患者及其健康一级进行横断面分析。 其次，我们将定义疾病发生前的狼疮特异性表观遗传模块。 通过在体外测定中操纵细胞因子来观察 TNF 家族成员对表观遗传景观的影响。 然后将检查接受 TNF 阻断治疗的患者的 CD4 + T 细胞，以直接定义 TNF 依赖性 最后，我们利用生物信息学方法来生成疾病特异性。 多种途径的富集分数，包括 TNF 依赖性信号传导和 I 型干扰素 有了这些信息，我们将确定临床疾病与表观遗传之间的关系。 我们的发现将带来以前不可能的详细程度的变化。 基因表达的遗传和表观遗传调控，并指出新的潜在治疗靶点 治疗和/或预防狼疮的干预措施。