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动脉粥样硬化的研究。 动脉粥样硬化性心血管疾病（ASCVD）的发病机制。IgG抗体诱导的一个靶点是 ASCVD患者的主要蛋白是载脂蛋白A-I（ApoA-I），是高密度脂蛋白（HDL）的主要蛋白。虽然反- ApoA-I抗体已在小鼠和人类受试者中鉴定，其作用尚未阐明。的PI 已经鉴定了在ApoA-I和IgG之间形成的免疫复合物（ApoA-I/IgGIC），其表现出抗炎性， 特征，并与降低CVD风险相关。对ApoA-I/IgG IC的持续评价将改善我们的 了解与ASCVD相关的免疫反应的这一组成部分。总的目标是 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。实现 为此，我们将对小鼠和患者血清样品中ApoA-I/IgG IC的分子组分进行表征 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。的 假设ApoA-I/IgGIC表现出通过抑制性Fc受体介导的抗炎作用 取决于抗体特征（即表位特异性，亚类），并且这些作用能够 抑制炎症和疾病。这项研究的基本原理是， 与ASCVD相关的体液免疫反应的组成部分将导致更好地理解ASCVD的免疫反应。 潜在的机制，并改善患者的结果。在强有力的初步数据的鼓舞下， 将通过两个具体目标进行测试：1）阐明分子组成和功能的影响， 使用培养细胞和动脉粥样硬化小鼠模型的ApoA-I/IgG IC;和2）确定特征 人血浆中ApoA-I/IgGIC的抗炎活性，并描述ApoA-I/IgGIC之间的相关性。 I/IgG IC和ASCVD在一个大型社区队列中。目标1将采用新的免疫调节策略， Venditto博士的实验室开发的，以实现抗体反应的表位特异性免疫调节， 小鼠以阐明抗体/表位功能和在动脉粥样硬化进展中的作用。目标2将使用血清 以表征抗体/表位功能并评价ApoA-I/IgG之间的关联 多种族动脉粥样硬化研究（梅萨）中的IC和疾病进展。方法是创新的 由于利用体内免疫调节方法来改变ApoA-I/IgGIC谱， 专注于获得患者中详细的ApoA-I/IgG IC谱，用于与疾病的关联研究。的 拟议的研究是重要的，因为这项研究的结果将提高我们对抗体的理解- 介导的对ApoA-I的免疫应答，以阐明抗体对ASCVD进展的作用。详细 前终末抗原、表位特异性、抗体亚类和受体结合的表征将 提高我们对ASCVD的理解，以指导治疗开发和未来的努力，以改善风险 分层程序，以减少患者的ASCVD负担。