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.

项目总结 近年来，先天免疫和获得性免疫都明显地促进了肺炎的发生。 高血压。我们发现了一种新的机制，它是激活适应性免疫的基础 高血压，包括在树突状细胞(DC)和其他抗原中形成异uglandins(IsUGs) 呈现细胞。这些脂质氧化产物加成到蛋白质上，导致形成新的抗原， 由主要组织相容性复合体(MHC)处理和呈递。IsoLG修饰的蛋白质是 高血压小鼠和人类的DC增加，并推动T细胞亚群的增殖， 尤其是CD8+T细胞。在这个研究项目中，我们正在研究负责形成 DC中的IsoLGs。我们有证据表明，isLGs的形成是NADPH氧化酶活化和 由DC中的线粒体产生的活性氧物种。使用我们制造的独一无二的老鼠 定义在MHC 1类中存在的潜在免疫原肽并确定是否存在不同的 线粒体来源的多肽与非线粒体来源的多肽。质谱学也将被 用来确定人类单核细胞是否呈递类似的等位基因修饰的多肽 高血压。与西蒙·马拉尔博士合作进行的平行研究，该中心主任 翻译免疫学核心在Vanderbilt，我们正在描述T的α和β链序列 用单细胞测序法测定小鼠和人活化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(转染瘤)，可以用来确定他们的 高血压小鼠对等Lg修饰的蛋白质和多肽的反应性。我们 最近研究表明，高血压患者的循环记忆T细胞显著增加 与对照组比较产生IL-17A和干扰素-γ。来自单细胞测序的数据将识别出 TcRα和TcRβ，并产生表达这些序列的转染瘤，并确定 它们也对来自同一个体的APC背景中出现的等LG修饰蛋白作出反应。 识别高血压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，并用于检测患者的致病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。 减少等低密度脂蛋白形成的特定疗法在实验模型中已被证明有效，并已 为人类高血压的治疗带来了巨大的希望。