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.

工程 摘要 狼疮 铅 是一种自身免疫性疾病，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抗体的产生有关 自身抗体(ANA)、免疫复合体的产生和组织损伤。全基因组关联 研究已经确定了导致疾病的&gt；100个易感基因；然而，细胞机制 这些基因的多态是如何导致细胞功能障碍的，目前尚不清楚。积累证据 提示狼疮的遗传易感性是通过改变细胞特异性的表观遗传学改变来调节的 转录档案。在初步实验中，我们发现了红斑狼疮特异的表观遗传学和 幼稚和效应的CD4+T细胞的转录特征。我们发现：1)表观遗传学 和 隔离物 和 已确定 易感性， 环境 细胞； 富化 团结在一起， 免疫学 天真的风景 狼疮患者活化的CD_4~+T细胞与正常人及S比较有显著差异 疾病；2)狼疮中大量的CD4+T细胞OCR存在于幼稚T细胞 先于T细胞激活；3)狼疮特异性OCR与易感等位基因不成比例地一致 在对狼疮的GWAS分析中。表观遗传悬挂可能是细胞固有的，次要于遗传的 并先于临床表现或细胞外源性免疫异常所致 在幼稚T细胞中存在疾病特异性通路提示狼疮的内在通路 分析表明，狼疮特有的特征是 在依赖于核因子-kB的DNA结合基序中，信号的下游通过肿瘤坏死因子家族成员。已被占用 我们的数据使我们假设L上皮炎的遗传易感性与狼疮有协同作用 在激活前改变造血细胞表观基因组的环境。 C 。 首先，我们将探索 狼疮的特征是开放的表观遗传图景是细胞固有的和先于细胞的假设 疾病。我们将通过刻画休眠的表观基因组来定义最小的造血狼疮特征 B细胞和单核细胞。我们将对患者和他们的健康一级进行横断面分析 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 在体外实验中，通过操纵细胞因子，肿瘤坏死因子家族成员对表观遗传格局的影响。我们 然后将检查接受肿瘤坏死因子阻断治疗的患者的CD4+T细胞，以直接确定肿瘤坏死因子依赖 表观遗传特征。最后，我们利用生物信息学的方法来产生特定于疾病的 包括肿瘤坏死因子依赖信号转导和I型干扰素在内的多个途径的浓缩分数 路径。有了这些信息，我们将确定临床疾病和表观遗传学之间的关系 变化的细节程度是以前不可能的。我们的发现将引导我们对 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 干预治疗和/或预防狼疮。