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，环境影响在允许的遗传背景中起作用 免疫失调。多种细胞类型的功能与抗核的产生有关 自身抗体（ANA），免疫复合物的产生和组织损伤。基因组广泛的关联 研究已经确定了有助于疾病的局部效果> 100个易感性。但是，细胞机制 这些多态性导致细胞功能障碍是未知的。积累证据 表明对狼疮的遗传敏感性是通过细胞特异性表观遗传变化介导的 转录曲线。非原则实验，我们确定了特异性表观遗传学和 幼稚和效应子CD4+ T细胞中的转录特征。我们发现：1）表观遗传 和 分离 和 确定 敏感性， 环境 细胞； 丰富 一起， 免疫学 天真的风景 与健康的供体和健康供体和 疾病； 2）狼疮中存在大量的CD4+ T细胞的OCR中存在于幼稚的T细胞中 在T细胞激活之前； 3）狼疮特异性的OCR与易感性等位基因不成比例 在狼疮的GWAS分析中。表观遗传悬挂可能是细胞中的，继发于遗传的 并在临床表现或细胞效力之前，由异常免疫学诱导 狼疮的内在途径是通过在幼稚T中存在疾病特异性途径的建议 通过分析表明狼疮特异性的特异性签名为 在NF-KB依赖性的DNA结合基序中，信号传导通过TNF家族成员。拍摄 我们的数据导致我们假设UPUS与狼疮合作的遗传倾向 在激活之前改变造血细胞的表观基因组的环境。 c 。 首先，我们将证明 表征狼疮的开放表观遗传景观的假设是细胞的固有，并且先于 疾病。我们将通过表征静息的表征来定义最小的造血狼疮签名 B细胞和单核细胞。我们将对患者及其健康的一级进行横断面分析 亲戚定义狼疮特异性的表观遗传模块。其次，我们将定义 TNF家族成员通过在体外测定中操纵细胞因子对表观遗传景观的影响。我们 然后，将检查用TNF阻滞治疗的患者中的CD4 + T细胞直接定义TNF依赖性 表观遗传学签名。最后，我们利用生物信息学方法来产生特异性疾病 多个途径的富集分数，包括依赖TNF的信号和I类干扰素 路径。有了这些信息，我们将确定临床疾病与表观遗传学之间的关系 以前是不可能的细节级别的变化。我们的发现将导致基本见解 基因表达的遗传和表观遗传调节，并指出了治疗的新型潜在靶标 干预以治疗和/或预防狼疮。