Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

项目摘要/摘要 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。 继续评估载脂蛋白A-I的详细抗体谱将提高我们对免疫的理解 与ASCVD相关的反应。这个项目的总体目标是阐明抗载脂蛋白A-I的作用 并研究其在ASCVD中的分子组成和功能影响。要做到这一点 目标，我们将在小鼠和患者中表征抗载脂蛋白A-I抗体反应的分子组成 血清样本，并将这些因素与细胞相互作用、功能结果和动脉粥样硬化相关 进步。假设抗载脂蛋白A-I抗体可以表现出促炎或抗炎作用 效果取决于特定抗体的特性(即抗原结合、亚类、表位特异性、 Fc受体相互作用)，这些效应在ASCVD患者中加剧或抑制。其基本原理是 这项拟议的研究是，理解体液免疫反应的一个组成部分与 ASCVD将导致对潜在机制的更好理解，并改善患者预后。这 假说将通过两个特定的目的来检验：1)阐明分子组成和功能 针对载脂蛋白A-I的抗体在小鼠动脉粥样硬化模型中的意义；以及2)描述这种联系 以社区为基础的大型前瞻性患者队列中抗体谱与ASCVD事件之间的关系。目标1将 使用Venditto博士的实验室开发的新免疫调节策略来实现表位特异性 抗体反应的调节以阐明抗体/表位的功能和在动脉粥样硬化进展中的作用。 在第二个目标中，来自动脉粥样硬化多种族研究(MESA)患者的血清将被评估 抗体谱，并与患者预后相关。这种方法是创新的，因为使用了In 体内免疫调节方法可以改变抗ApoA-I免疫球蛋白谱，以及我们获得表位的能力- 对小鼠的特异性免疫抑制。作为本研究的成果，本文的研究具有重要意义。 将提高我们对B细胞介导的免疫应答载脂蛋白A-I的理解，以阐明抗体的作用 关于ASCVD的进展。抗原、表位特异性、抗体亚类和 受体参与将加强对ASCVD的了解，以指导治疗开发和未来的努力 改进患者危险分层程序，减轻ASCVD患者的负担。

PROJECT SUMMARY/ABSTRACT 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. Continued evaluation of the detailed antibody profile of ApoA-I will improve our understanding of the immune responses associated with ASCVD. The overall goal of this project is to elucidate the role of anti-ApoA-I antibodies and to characterize their molecular composition and functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of the anti-ApoA-I antibody response in mice and patient serum samples and correlate these factors with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I antibodies can exhibit a pro-inflammatory or anti-inflammatory effect, depending on the specific antibody characteristics (i.e., antigen engagement, subclass, epitope specificity, Fc receptor interaction), and these effects are exacerbated or suppressed in ASCVD patients. 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 improved patient outcomes. This hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting ApoA-I in mouse models of atherosclerosis; and 2) Delineate the association between antibody profiles and ASCVD events in a large community-based prospective patient cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific modulation of antibody responses to elucidate antibody/epitope function and role in atherosclerosis progression. In the second aim, sera from patients in the Multi-Ethnic Study of Atherosclerosis (MESA) will be evaluated for antibody profiles and correlated with patient outcomes. The approach is innovative due to the utilization of in vivo immunomodulation approaches that can alter the anti-ApoA-I IgG profiles, and our ability to achieve epitope- specific immune suppression in mice. The proposed research is significant as the outcomes of this research will improve our understanding of B cell-mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures in patients to decrease the burden of ASCVD in patients.