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

项目总结/摘要-项目4 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。 心血管疾病（CVD）的发病机制。抗原的详细表征，表位特异性， 抗体亚类和受体结合将增强对CVD的理解， 发展患者中IgG抗体诱导的一个靶点是载脂蛋白A-I（ApoA-I），其是免疫球蛋白的主要蛋白质。 高密度脂蛋白（HDL）。尽管已经在小鼠和人类受试者中鉴定出抗ApoA-I抗体， 这些抗体的作用尚未阐明。此外，结合抗体的免疫学影响 免疫复合物（ApoA-I/IgG IC）中ApoA-I的表达尚不清楚。长期目标是开发新的肽 以及基于小鼠的机理洞察的抗体治疗，以减轻患者的CVD负担。到 为了实现这一目标，本提案的总体目标建立在我们对人类受试者的观察基础上， 表征小鼠中抗ApoA-I抗体应答的分子组分，并将其与 特征与细胞相互作用、功能结果和动脉粥样硬化进展。的假设 抗ApoA-I抗体根据抗体表现出促炎和抗炎作用 导致恶化或抑制的特征（即亚类、表位特异性、Fc受体相互作用） 动脉粥样硬化这项研究的基本原理是，了解免疫系统的一个组成部分， 与CVD相关的反应将通过新的治疗策略促进改善患者结局。 在强有力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 靶向来自于以下的肽表位的抗体的分子组分和功能含义 ApoA-I;和2）通过与ApoA-I/IgG IC结合来确定ApoA-I/IgG IC是否介导抗炎表型。 在动脉粥样硬化易感小鼠模型中使用体外测定和体内研究来测定抑制性Fc受体。上 目的是，通过计算机模拟、生物物理学和免疫原性相关性， 来源于ApoA-I的已知肽表位的表征和免疫原性研究。这些数据将 与针对ApoA-I的抗体应答的抗体谱和亚类组成相关。在 第二个目的是，通过表征细胞的特性来确定抗ApoA-I抗体的机制影响。 在动脉粥样硬化易感者中存在特异性抗ApoA-I谱和诱导抗体谱的极化 缺乏Fc受体的小鼠。本文的创新性和意义是由小说驱动的 免疫调节策略，这将提高我们对抗体介导的免疫反应的理解， 这将指导通过与CPRI COBRE协调开发新的免疫疗法的持续努力， 降低患者的CVD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.