Mechanisms of Immune Activation in Hypertension

高血压的免疫激活机制

• 批准号: 10328922
• 负责人: David G Harrison
• 金额: $ 75.17万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328922
• 关键词: Adult; Affect; Antigen-Presenting Cells; Biological Markers; CD8-Positive T-Lymphocytes; Cells; Collaborations; Data; Dendritic Cells; Disease; Experimental Models; Healthcare; Histocompatibility Antigens Class I; Human; Hypertension; Immunization; Immunology; Individual; Inflammation; Interferon Type II; Interleukin-17; Kidney Diseases; Lipids; Major Histocompatibility Complex; Mass Spectrum Analysis; Mitochondria; Mus; Myocardial Infarction; NADPH Oxidase; Natural Immunity; Pathogenicity; Peptides; Process; Proteins; Public Health; Reactive Oxygen Species; Research; Severity of illness; Source; Stroke; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; United States; adaptive immunity; adduct; care burden; hypertensive; immune activation; immunogenic; monocyte; neoantigens; novel; oxidation; prevent; programs; single cell sequencing

PROJECT SUMMARY In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells, particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are defining potential immunogenic peptides presented in MHC class 1 and determining if there are different peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be employed to determine if similar isoLG modified peptides are presented by monocytes of humans with hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T cell receptors (TCRα and TCRβ) in activated T cells of both mice and humans using single cell sequencing. This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We have recently shown that hypertensive humans have a striking increase in circulating memory T cells that produce IL-17A and IFN-γ compared to matched controls. Data from single cell sequencing will identify the TCRα and TCRβ of these cells and to produce transfectomas expressing these sequences and to determine if they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual. Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension. Specific therapies to reduce isoLG formation have proven effective in experimental models and have substantial promise for treatment of human hypertension.

项目概要 近年来，越来越明显的是，先天性免疫和适应性免疫都有助于疾病的发生。 高血压。我们发现了一种新的机制，它是适应性免疫激活的基础 高血压，涉及树突状细胞 (DC) 和其他抗原中异黄酮素 (isoLG) 的形成 呈现细胞。这些脂质氧化产物与蛋白质加合，导致形成新抗原， 由主要组织相容性复合体 (MHC) 加工和呈递。 IsoLG 修饰的蛋白质是 患有高血压的小鼠和人类的 DC 数量增加，并驱动 T 细胞亚群增殖， 特别是 CD8+ T 细胞。在这个研究项目中，我们正在研究负责形成的机制 DC 中的 isoLG。我们有证据表明 isoLG 的形成是 NADPH 氧化酶激活和 由 DC 中线粒体产生的活性氧产生。使用我们制造的独特鼠标 定义 MHC 1 类中存在的潜在免疫原性肽并确定是否存在不同 线粒体来源的肽与非线粒体来源的肽。质谱分析也将 用于确定类似的 isoLG 修饰肽是否由人类单核细胞呈递 高血压。在与该中心主任 Simon Mallal 博士合作进行的平行研究中， 范德比尔特大学的转化免疫学核心，我们正在表征 T 的 α 和 β 链序列 使用单细胞测序对小鼠和人类激活的 T 细胞中的细胞受体（TCRα 和 TCRβ）进行分析。 这将使我们能够生产替代 T 细胞（转染瘤），用于确定其 对高血压小鼠 MHC 1 类中存在的 isoLG 修饰蛋白和肽的反应性。我们 最近的研究表明，高血压人群的循环记忆 T 细胞显着增加， 与匹配对照相比，产生 IL-17A 和 IFN-γ。来自单细胞测序的数据将识别 这些细胞的TCRα和TCRβ并产生表达这些序列的转染瘤并确定是否 它们还对来自同一个体的 APC 中存在的 isoLG 修饰蛋白做出反应。 识别高血压中的特定新抗原将为理解这一点提供巨大的进步 疾病。这些可以作为疾病严重程度的生物标志物，并用于检测致病性 T 细胞 高血压。最终可以采用免疫方法来治疗或预防高血压。 减少 isoLG 形成的特定疗法已在实验模型中被证明是有效的，并且已被证明是有效的。 治疗人类高血压的巨大前景。