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 总结 狼疮 铅 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， 多种细胞类型的功能障碍与抗核抗体的产生有关。 自身抗体（ANA）、免疫复合物的产生和组织损伤。全基因组关联 研究已经确定了>100个易感基因座，有助于疾病;然而，细胞机制， 这些多态性通过何种途径导致细胞功能障碍尚不清楚。越来越多的证据 表明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， 转录谱在初步的实验中，我们确定了alupus特定的表观遗传和 初始和效应CD 4 + T细胞中的转录特征。我们发现：1）表观遗传 和 偏析 和 识别 敏感性， milieu 细胞; 丰富 在一起， 免疫 天真的风景 活化的CD 4 + T细胞在狼疮患者中与健康供体相比存在显著差异， 2）狼疮中大量的CD 4 + T细胞的OCR存在于幼稚T细胞中 在T细胞活化之前; 3）狼疮特异性OCR与易感性等位基因不成比例地对齐 GWAS对狼疮的分析。表观遗传的改变可能是细胞内在的，继发于遗传的， 并先于临床表现或细胞外源性和异常免疫诱导 内在途径是由一个疾病特异性途径的存在，在天真的T 炎症的外在效应是通过分析表明狼疮特异性信号是 在通过TNF家族成员的信号传导下游的NF-kB依赖性DNA结合基序中。采取 我们的数据使我们假设狼疮的遗传易感性与狼疮协同作用， 造血干细胞的表观基因组在活化前改变。 C . 首先，我们将探索 这一假说认为，开放的表观遗传景观的特点狼疮是细胞内在的，并先于 疾病我们将定义最小的造血系统狼疮签名的特点，表观基因组休息 B细胞和单核细胞。我们将对患者及其健康的第一学位进行横断面分析 亲属来定义疾病之前的狼疮特异性表观遗传模块。其次，我们将定义 TNF家族成员通过在体外试验中操纵细胞因子对表观遗传景观的影响。我们 然后将检查接受TNF阻断治疗的患者中的CD 4 + T细胞，以直接确定TNF依赖性T细胞。 表观遗传特征最后，我们利用生物信息学方法生成疾病特异性 多种途径的富集评分，包括TNF依赖性信号传导和I型干扰素 通路有了这些信息，我们将确定临床疾病和表观遗传之间的关系 在以前不可能的细节水平上进行了改变。我们的研究结果将导致基本的见解， 基因表达的遗传和表观遗传调控，并指出新的潜在的治疗目标 干预以治疗和/或预防狼疮。