Autoimmunity as a Mechanism for Atherosclerosis in COPD

 描述（由申请人提供）：本项目将促进主要研究者发展为独立的转化研究者，研究慢性阻塞性肺疾病（COPD）的全身血管损伤。这将在匹兹堡大学丰富的学术环境中完成，在一个非常有成就的导师团队的指导下，并在多学科研究项目的开展中完成，该项目将开发自身免疫作为COPD动脉粥样硬化的一种新机制。吸烟、年龄、高血压和其他已确定的血管疾病危险因素不能解释COPD患者动脉粥样硬化风险的增加。慢性炎症最近被认为是COPD的致动脉粥样硬化机制。我们和其他人已经报道慢性阻塞性肺疾病的慢性炎症可能通过体液自身免疫传播。具体而言，患有COPD的吸烟者的循环自身抗体水平大大增加，这些抗体在体外表现出致病作用。我们随后的研究还表明，这些自身抗体靶向至少50种不同的自身抗原，并始终靶向葡萄糖调节蛋白78（GRP 78），特别是在肺实质破坏（即肺气肿）患者中。GRP 78存在于内质网中，在那里它调节未折叠的蛋白质反应，并且也是多功能细胞表面受体。在癌症患者中的研究表明，通过抗GRP 78 IgG连接细胞表面GRP 78的N末端，通过激活AKT途径，随后激活NFκB，转导促炎和促增殖信号。附加的 体内研究已经鉴定了对细胞表面GRP 78的C末端具有亲和力的抗GRP 78 IgG，其通过抑制AKT活化而产生抵消抗炎作用。我们的初步工作表明，COPD患者循环中的抗GRP 78 IgG与巨噬细胞结合，导致NFκB活化增加，并通过它们产生致动脉粥样硬化的炎症介质。巨噬细胞在动脉粥样硬化和COPD的发展中至关重要。此外，我们队列的横断面研究发现，循环抗GRP 78 IgG水平与肺气肿患者的颈动脉粥样硬化密切相关，独立于已建立的血管风险因素。因此，我们假设针对GRP 78的自身免疫反应是COPD动脉粥样硬化的一种机制。（1）在4年的随访中，检验循环抗GRP 78 IgG水平升高预测肺气肿患者颈动脉粥样硬化进展的假设，该假设独立于已确定的危险因素;（2）检验抗GRP 78 IgG结合N-GRP的假设。细胞表面GRP 78的末端，并激活AKT途径，随后是NFκB激活和炎症介质的产生，并为两种潜在的治疗策略提供概念证明;（3）通过使用机器学习分析大量循环自身抗体水平的高通量数据，测试COPD中存在与动脉粥样硬化相关的其他抗原特异性免疫应答的假设。

 DESCRIPTION (provided by applicant): This project will facilitate the development of the principal investigator into an independent translational researcher investigating systemic vascular injury in Chronic obstructive pulmonary disease (COPD). This will be accomplished in the rich academic environment at the University of Pittsburgh, under the guidance of a highly accomplished team of mentors, and in the conduct of multidisciplinary research project that will develop autoimmunity as a novel mechanism for atherosclerosis in COPD. The increased risk of atherosclerosis in COPD is not explained by smoking, age, hypertension, and other established vascular disease risk factors. Chronic inflammation has recently been implicated as an atherogenic mechanism in COPD. We and others have reported that chronic inflammation in COPD may be propagated by humoral autoimmunity. Specifically, smokers with COPD have greatly increased levels of circulating autoantibodies that demonstrate in vitro pathogenic effects. Our subsequent studies also show that these autoantibodies target at least 50 different autoantigens and consistently target glucose regulated protein 78 (GRP78), particularly in patients with parenchymal lung destruction, i.e. emphysema. GRP78 is present in the endoplasmic reticulum, where it regulates the unfolded protein response, and is also a multifunction cell surface receptor. Studies in cancer patients suggest that ligation of the N-terminus of cell surface GRP78 by anti-GRP78 IgG transduces pro-inflammatory and pro-proliferative signals by activation of the AKT pathway, followed by NFκB activation. Additional in vivo studies have identified anti-GRP78 IgG with affinity for the C-terminus of cell surface GRP78 that produce counteracting anti-inflammatory effects by suppressing AKT activation. Our preliminary work shows that circulating anti-GRP78 IgG in COPD patients binds to macrophages and leads to increased NFκB activation and production of atherogenic inflammatory mediators by them. The macrophage is critical in the development of both atherosclerosis and COPD. Also, cross-sectional studies in our cohort find that levels of circulating anti-GRP78 IgG are strongly associated with carotid atherosclerosis in patients with emphysema, independent of established vascular risk factors. Therefore, we hypothesize that autoimmune responses against GRP78 are a mechanism for atherosclerosis in COPD. During this award, we will: (1) Test the hypothesis that elevated levels of circulating anti-GRP78 IgG predict progression of carotid atherosclerosis in patients with emphysema independent of established risk factors over 4 year follow up; (2) Test the hypothesis that anti-GRP78 IgG binds to the N-terminus of cell surface GRP78 and activates the AKT pathway followed by NFκB activation and production of inflammatory mediators using a variety of cell function assays, and provide proof of concept for two potential therapeutic strategies; (3) Test the hypothesis that there are other antigen-specific immune responses associated with atherosclerosis in COPD by using machine learning to analyze high-throughput data on a large number of circulating autoantibody levels.