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

项目摘要/摘要--项目4 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 心血管疾病的发病机制。抗原的详细特征，抗原表位的特异性， 抗体亚类和受体结合有助于提高对心血管疾病的认识和指导治疗 发展。在患者中诱导免疫球蛋白抗体的一个靶点是载脂蛋白A-I(ApoA-I)，载脂蛋白A-I是 高密度脂蛋白(HDL)。虽然已经在老鼠和人类受试者中发现了抗载脂蛋白A-I抗体， 这些抗体的作用尚未阐明。此外，抗体结合的免疫学影响 免疫复合体(ApoA-I/Ig G IC)中ApoA-I与ApoA-I的结合尚不清楚。长期目标是开发新的多肽 以及基于对小鼠的机械洞察力的抗体疗法，以减轻患者的心血管疾病负担。至 实现这一目标，这项建议的总体目标建立在我们对人类受试者的观察基础上 鉴定小鼠抗载脂蛋白A-I抗体反应的分子组成及其相互关系 细胞相互作用、功能结果和动脉粥样硬化进展的特征。假说 抗ApoA-I抗体根据抗体表现出促炎和抗炎作用 导致加重或抑制的特征(即亚类、表位特异性、Fc受体相互作用) 动脉粥样硬化。这项拟议研究的基本原理是，了解免疫的一个组成部分 与心血管疾病相关的反应将通过新的治疗策略促进患者预后的改善。 在强劲的初步数据的鼓舞下，这一假设将通过两个具体目标进行检验：1)阐明 猪源多肽表位抗体的分子组成及其功能意义 ApoA-I；以及2)确定ApoA-I/Ig G IC是否通过与 在动脉粥样硬化易感受性小鼠模型中使用体外分析和体内研究抑制Fc受体。在第一个 目的：通过计算机模拟、生物物理关联来生成结构免疫原性关系 ApoA-I已知多肽表位的鉴定及免疫原性研究这些数据将是 与抗体谱和ApoA-I抗体反应的亚类组成相关。在 第二个目的是通过鉴定细胞特性来确定抗载脂蛋白A-I抗体的作用机制 动脉粥样硬化患者抗载脂蛋白A-I特异谱和诱导抗体谱的极化 缺乏Fc受体的小鼠。这部作品的创新和意义是由这部小说驱动的 免疫调节策略将提高我们对抗体介导的免疫反应的理解， 它将通过与CPRI Cobre的协调，指导继续努力开发新的免疫疗法， 减轻患者心脑血管疾病负担。

PROJECT SUMMARY / ABSTRACT – PROJECT 4 The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of cardiovascular disease (CVD). Detailed characterization of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance the understanding of CVD and guide therapeutic development. One target of IgG antibody induction in 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, the role of these antibodies have not been elucidated. Furthermore, the immunologic impact of antibodies bound to ApoA-I in an immune complex (ApoA-I/IgG ICs) is unclear. The long-term goal is to develop novel peptide and antibody therapeutics based on mechanistic insight from mice, to reduce the burden of CVD in patients. To achieve this goal, the overall objectives of this proposal build from our observations in human subjects to characterize the molecular components of the anti-ApoA-I antibody response in mice and correlate their characteristics with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I antibodies exhibit both pro- and anti-inflammatory effects depending on the antibody characteristics (i.e. subclass, epitope specificity, Fc receptor interaction) leading to exacerbation or suppression of atherosclerosis. The rationale for this proposed research is that understanding one component of the immune response associated with CVD will promote improved patient outcomes through novel therapeutic strategies. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting peptide epitopes derived from ApoA-I; and 2) Determine if ApoA-I/IgG ICs mediate an anti-inflammatory phenotype by engaging with the inhibitory Fc receptor using in vitro assays and in vivo studies in atherosusceptible mouse models. In the first aim, a structure immunogenicity relationship will be generated by correlating in silico modeling, biophysical characterization and immunogenicity studies of known peptide epitopes derived from ApoA-I. These data will be correlated with antibody profiles and subclass composition of the antibody response toward ApoA-I. In the second aim, the mechanistic impact of anti-ApoA-I antibodies will be determined by characterizing cell polarization in the presence of specific anti-ApoA-I profiles and inducing antibody profiles in atherosusceptible mice lacking Fc receptors. The innovation and significance of the proposed work is driven by the novel immunomodulation strategies that will improve our understanding of antibody-mediated immune responses, which will guide continued efforts to develop novel immunotherapies through coordination with the CPRI COBRE, to decrease the burden of CVD in patients.