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

动脉粥样硬化斑块中自身抗原的鉴定促进了抗体介导的研究 动脉粥样硬化性心血管疾病的发病机制。免疫球蛋白G抗体诱导的一个靶点 ASCVD患者是载脂蛋白A-I(ApoA-I)，是高密度脂蛋白(HDL)的主要蛋白。尽管反- 载脂蛋白A-I抗体已在小鼠和人类受试者中被鉴定，其作用尚未阐明。《少年派》 已确定ApoA-I和Ig G之间形成的免疫复合物(ApoA-I/Ig G IC)具有抗炎作用 这些特征与降低心血管疾病风险有关。对ApoA-I/Ig G 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。这个项目的总体目标是 本项目旨在确定ApoA-I/IgICs在ASCVD中的作用，并阐明其在ASCVD中的作用。要实现 为了达到这个目标，我们将在小鼠和患者血清样本中鉴定载脂蛋白A-I/免疫球蛋白ICs的分子组成 并将这些因素与细胞相互作用、功能结果和疾病进展联系起来。这个 假设ApoA-I/Ig G ICs通过抑制Fc受体发挥抗炎作用 取决于抗体特性(即表位特异性、亚类)，而这些效应能够 抑制炎症和疾病。这项拟议研究的基本原理是理解一项 与ASCVD相关的体液免疫反应的成分将有助于更好地理解 潜在的机制和改善患者的预后。在强劲的初步数据的鼓舞下，这一假设 将通过两个特定的目的进行测试：1)阐明分子组成和功能含义 利用培养细胞和小鼠动脉粥样硬化模型建立载脂蛋白A-I/免疫球蛋白IC；2)确定 和人血浆载脂蛋白A-I/Ig G细胞的抗炎活性，并描绘了载脂蛋白A-I/Ig G-ICs与 以社区为基础的大型队列中的I/Ig G IC和ASCVD。AIM 1将采用新的免疫调节策略， 在Venditto博士的实验室开发，以实现表位特异性的抗体反应的免疫调节 小鼠阐明抗体/表位功能及其在动脉粥样硬化进展中的作用。AIM 2将使用血清 鉴定抗体/表位功能并评价载脂蛋白A-I/免疫球蛋白之间的相关性 动脉粥样硬化(MESA)多种族研究中的ICS和疾病进展。这种方法是创新的 由于利用体内免疫调节方法改变载脂蛋白A-I/Ig G IC谱，以及我们的方法 重点是获得患者详细的载脂蛋白A-I/免疫球蛋白IC图谱，用于与疾病的相关性研究。这个 拟议的研究具有重要意义，因为这项研究的结果将提高我们对抗体- ApoA-I介导的免疫反应以阐明抗体在ASCVD进展中的作用。详细 预定型抗原、表位特异性、抗体亚类和受体结合的特征 加强我们对ASCVD的了解，以指导治疗发展和未来改善风险的努力 分层程序，以减轻ASCVD患者的负担。

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.