Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease

了解载脂蛋白 A-I 和 IgG 之间的免疫复合物在动脉粥样硬化性心血管疾病中的作用

• 批准号: 10431791
• 负责人: Vincent Joseph Venditto
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431791
• 关键词: Anti-Inflammatory Agents; Antibodies; Antibody Response; Antigen-Antibody Complex; Antiinflammatory Effect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Autoantibodies; Autoantigens; Autoimmunity; Blood Circulation; Cardiovascular Diseases; Cell model; Cells; Characteristics; Communities; Complex; Cultured Cells; Data; Death Rate; Development; Disease; Disease Progression; Epitopes; Evaluation; Event; Exhibits; Fc Receptor; Foundations; Future; Goals; High Density Lipoproteins; Homeostasis; Human; IgG4; Immune Complex Diseases; Immune response; Immunization; Immunoglobulin G; Incidence; Inflammation; Investigation; Laboratories; Measures; Mediating; Molecular; Multi-Ethnic Study of Atherosclerosis; Multivariate Analysis; Mus; Myocardial Infarction; Outcome; Outcomes Research; Participant; Pathogenesis; Patient-Focused Outcomes; Patients; Phenotype; Plant Roots; Plasma; Procedures; Prospective cohort; Proteins; Protocols documentation; Receptor Signaling; Research; Risk; Risk Factors; Role; Sampling; Specificity; Stroke; Testing; adjudicate; base; burden of illness; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; clinical risk; cohort; drug development; follow-up; functional outcomes; human subject; immunoregulation; improved; in vitro activity; in vivo; innovation; male; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; obese patients; profiles in patients; programs; protocol development; receptor; response; risk stratification; therapeutic development; treatment strategy; vaccination strategy; western diet

The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction in ASCVD patients is apolipoprotein A-I (ApoA-I), the major protein of high density lipoprotein (HDL). Although anti- ApoA-I antibodies have been identified in mice and human subjects, their role has not been elucidated. The PI has identified immune complexes formed between ApoA-I and IgG (ApoA-I/IgG IC) that exhibit anti-inflammatory characteristics and associate with decreased CVD risk. Continued evaluation of ApoA-I/IgG ICs will improve our understanding of this component of the immune responses associated with ASCVD. The overall goal of this project is to determine the role of ApoA-I/IgG ICs and elucidate their functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of ApoA-I/IgG ICs in mouse and patient sera samples and correlate these factors with cellular interactions, functional outcomes and disease progression. The hypothesis is that ApoA-I/IgG ICs exhibit anti-inflammatory effects mediated through the inhibitory Fc-receptor depending on antibody characteristics (i.e. epitope specificity, subclass), and these effects are capable of suppressing inflammation and disease. The rationale for this proposed research is that understanding one component of the humoral immune response associated with ASCVD will lead to a better understanding of the underlying mechanisms and improve patient outcomes. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of ApoA-I/IgG ICs using cultured cells and mouse models of atherosclerosis; and 2) Determine the characteristics and anti-inflammatory activity of ApoA-I/IgG ICs from human plasma and delineate the association among ApoA- I/IgG ICs and ASCVD in a large community-based cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific immune modulation of antibody responses in mice to elucidate antibody/epitope function and the role in atherosclerosis progression. Aim 2 will employ sera from human subjects to characterize antibody/epitope function and evaluate the association between ApoA-I/IgG ICs and disease progression in the Multi-Ethnic Study of Atherosclerosis (MESA). The approach is innovative due to the utilization of in vivo immunomodulation approaches to alter ApoA-I/IgG IC profiles, and our approach focused on obtaining detailed ApoA-I/IgG IC profiles in patients for association studies with disease. The proposed research is significant as the outcomes of this research will improve our understanding of antibody- mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the prefinalantigen, epitope specificity, antibody subclass and receptor engagement will enhance our understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures to decrease the burden of ASCVD in patients.

动脉粥样硬化斑块中自身抗原的鉴定促进了对抗体介导的抗体介导的研究 动脉粥样硬化性心血管疾病（ASCVD）的发病机制。 IgG 抗体诱导的靶标之一 ASCVD患者的载脂蛋白A-I（ApoA-I）是高密度脂蛋白（HDL）的主要蛋白质。虽然反 ApoA-I 抗体已在小鼠和人类受试者中被发现，但其作用尚未阐明。 PI 已鉴定出 ApoA-I 和 IgG (ApoA-I/IgG IC) 之间形成的具有抗炎作用的免疫复合物 特征并与 CVD 风险降低相关。对 ApoA-I/IgG IC 的持续评估将改善我们的 了解与 ASCVD 相关的免疫反应的这一组成部分。本次活动的总体目标 该项目旨在确定 ApoA-I/IgG IC 的作用并阐明其在 ASCVD 中的功能影响。达到 为了实现这一目标，我们将表征小鼠和患者血清样本中 ApoA-I/IgG IC 的分子成分 并将这些因素与细胞相互作用、功能结果和疾病进展相关联。这 假设 ApoA-I/IgG IC 通过抑制性 Fc 受体介导发挥抗炎作用 取决于抗体特征（即表位特异性、亚类），这些效应能够 抑制炎症和疾病。这项拟议研究的基本原理是，了解一个 与 ASCVD 相关的体液免疫反应的组成部分将有助于更好地了解 潜在的机制并改善患者的治疗结果。受到强有力的初步数据的鼓舞，这一假设 将通过两个具体目标进行测试：1）阐明分子成分和功能含义 使用培养细胞和动脉粥样硬化小鼠模型的 ApoA-I/IgG IC； 2) 确定特性 人血浆中 ApoA-I/IgG IC 的抗炎活性和抗炎活性，并描绘了 ApoA-I/IgG IC 之间的关联 基于社区的大型队列中的 I/IgG IC 和 ASCVD。目标 1 将采用新型免疫调节策略， Venditto 博士实验室开发的，可实现抗体反应的表位特异性免疫调节 小鼠阐明抗体/表位功能以及在动脉粥样硬化进展中的作用。目标2将使用血清 来自人类受试者的抗体/表位功能特征并评估 ApoA-I/IgG 之间的关联 动脉粥样硬化多种族研究 (MESA) 中的 IC 和疾病进展。该方法具有创新性 由于利用体内免疫调节方法来改变 ApoA-I/IgG IC 谱，以及我们的方法 专注于获取患者详细的 ApoA-I/IgG IC 图谱，以进行与疾病的关联研究。这 拟议的研究意义重大，因为这项研究的结果将提高我们对抗体的理解 介导对 ApoA-I 的免疫反应，以阐明抗体对 ASCVD 进展的作用。详细的 预最终抗原、表位特异性、抗体亚类和受体结合的特征将 增强我们对 ASCVD 的理解，以指导治疗开发和未来降低风险的努力 分层程序以减轻患者 ASCVD 的负担。