Mechanisms of Immune Activation in Hypertension

高血压的免疫激活机制

• 批准号: 10543181
• 负责人: David G Harrison
• 金额: $ 75.15万
• 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/10543181
• 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; IL17 gene; Immunization; Individual; Inflammation; Interferon Type II; Kidney Diseases; Lipids; Major Histocompatibility Complex; Mass Spectrum Analysis; Mitochondria; Mus; Myocardial Infarction; NADPH Oxidase; Natural Immunity; Pathogenicity; Peptides; Process; Proliferating; Proteins; Public Health; Reactive Oxygen Species; Research; Severity of illness; Source; Stroke; T memory cell; T-Cell Activation; 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; translational immunology

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.

项目摘要 近年来，显而易见的是，先天和适应性免疫学都有助于 高血压。我们发现了一种新型机制，该机制是基于适应性免疫学激活的基础 高血压，涉及树突状细胞（DC）和其他抗原的异戊瓜素（Isalgs）的形成 呈现细胞。这些脂质氧化产物加合成蛋白质，从而形成新抗原， 由主要的组织相容性复合物（MHC）处理和提出。分离的蛋白质是 小鼠和人类的DC增加，高血压并驱动T细胞亚群的增殖， 特别是CD8+ T细胞。在该研究计划中，我们正在研究负责形成的机制 DC中的隔离。我们有证据表明，由于NADPH氧化物激活和 通过线粒体在DC中产生的活性氧。使用我们使我们的独特老鼠是 定义MHC 1类中呈现的潜在免疫原性Petides并确定是否有不同 源自线粒体与非线粒体来源的肽。质谱也将是 用于确定是否由人类的单核细胞提出了类似的分离型肽 高血压。在与Simon Mallal博士合作进行的并行研究中， 范德比尔特（Vanderbilt）的转化免疫学核心，我们正在表征t的alpha和beta链序列 使用单细胞测序，在小鼠和人类活化的T细胞中的细胞受体（TCRα和TCRβ）。 这将使我们能够产生替代T细胞（转化切除术），可用于确定其 对高血压小鼠MHC 1类中呈现的分离蛋白和肽的反应。我们 最近表明，高血压的人在循环记忆T细胞中的罢工增加 与匹配的对照组相比，产生IL-17A和IFN-γ。来自单细胞测序的数据将确定 这些细胞的TCRα和TCRβ，并产生表达这些序列的跨膜切除术，并确定是否是否 它们还对来自同一个体的APC的背景下呈现的Iselg修饰蛋白有反应。 在高血压中识别特定的新抗原将为理解这一点提供巨大的进步 疾病。这些可以用作疾病严重程度的生物标志物，并用于检测病原T细胞 高血压。最终可以聘请免疫抑制方法来治疗或防止高血压。 在实验模型中证明了减少分离形成的特定疗法已被证明有效，并具有 治疗人类高血压的实质性希望。