Immune-mediated pathways in pathogenesis of abdominal aortic aneurysm

描述（由申请人提供）： 本提案的长期目标是阐明腹主动脉瘤（AAA）形成和进展的病理生理机制。AAA是一种常见且可能致命的血管疾病，影响高达9%的65岁及以上的个体。AAA是一种与男性、高血压、动脉粥样硬化、冠状动脉疾病和吸烟相关的复杂疾病。它是美国20大主要死亡原因之一，每年约有15，000人死亡。据估计，50岁以上的美国退伍军人中，每20人中就有1人患有AAA。AAA的治疗选择目前仅限于手术干预。大型AAA（直径大于5.5 cm）的开放手术修复是预防破裂死亡的有效选择。虽然有效，但开放性手术修复可能与高术后死亡率（高达6%）相关。考虑到有限的治疗选择，AAA患者的高龄可能使他们无法接受手术，因此药物治疗以减缓进展是一种有吸引力的选择。 本申请的目的是进一步了解参与AAA的免疫介导的途径。越来越多的证据表明AAA是一种炎症性免疫介导的疾病。使用弹性蛋白酶诱导的AAA小鼠模型，概括了人类AAA的许多关键特征，我们以前建立了一个自身抗体通过补体激活指导动脉瘤的发展。我们随后克隆了一种特异于纤维蛋白原的致病性IgG自身抗体，它能与小鼠的弹性蛋白酶灌注的主动脉壁组织结合， 补体凝集素途径（LP）上游的旁路途径（AP），并诱导AAA形成。此外，我们证明，在人类AAA组织中，纤维蛋白原与甘露聚糖结合凝集素（MBL），LP的一个重要组成部分，共定位，这表明，在人类中的纤维蛋白原的识别可能会启动补体激活。此外，我们发现，循环自身抗体在一个子集的个人与AAA的反应，对纯化的纤维蛋白原， 体外和纤维蛋白原相关的表位在人类囊性组织，进一步加强了我们的实验结果的相关性。补体激活导致产生过敏毒素（C3 a和C5 a），将中性粒细胞吸引到主动脉壁。一旦被募集，中性粒细胞释放中性粒细胞胞外陷阱（NET），其可能调节适应性（T细胞）应答。最后，我们确定了CD 8 + T细胞在中性粒细胞募集下游的动脉瘤发生中起关键作用。 几个悬而未决的问题仍然存在：1）是什么机制，触发自身免疫对蛋白质（纤维蛋白原）大量发现在循环; 2）是什么事件，连接中性粒细胞和NET的慢性，适应性免疫（T细胞）反应，和3）T细胞如何传播炎症级联反应，导致最终的血管扩张。我们认为，对AAA中免疫过程的彻底调查将为管理动脉瘤发生的机制提供新的见解，并为基于免疫的医学疗法确定潜在的治疗靶点。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the pathophysiological mechanisms underlying abdominal aortic aneurysm (AAA) formation and progression. AAA is a common and potentially fatal vascular condition affecting up to 9% of individiuals age 65 and older. AAA is a complex disease associated with male gender, hypertension, atherosclerosis, coronary artery disease, and cigarette smoking. It is among the top twenty leading causes of death in the United States, accounting for approximately 15,000 deaths per year. It is estimated that as many as 1 in 20 U.S. veterans over the age of 50 have AAA. Treatment option for AAA is currently limited to surgical intervention. Open surgical repair of large AAA (greater than 5.5 cm in diameter) is an effective option in preventing death from ruptures. Although effective, open surgical repair can be associated with high post-operative mortality (up to 6%). Given the limited treatment options, the advanced age of patients with AAA-which may preclude them from undergoing surgery- medical treatment to slow progression thus represents an attractive alternative. The objective of this application is to further the understanding of immune-mediated pathways involved in AAA. Increasing evidence suggests that AAA is an inflammatory, immune-mediated disease. Using an elastase-induced AAA mouse model that recapitulates many key features of human AAA, we previously established that an autoantibody directs aneurysm development through complement activation. We subsequently cloned a pathogenic IgG autoantibody specific for fibrinogen that binds to elastase-perfused aortic wall tissues in the mouse, activates the complement lectin pathway (LP) upstream of the alternative pathway (AP), and induces AAA formation. Additionally we demonstrate that, in human AAA tissues, fibrinogen colocalizes with mannan-binding lectin (MBL), an essential component of the LP, suggesting that recognition of fibrinogen may initiate complement activation in humans as well. Moreover, we found that circulating autoantibodies in a subset of individuals with AAA react against purified fibrinogen in vitro and fibrinogen- associated epitopes in human aneurysmal tissues, further enhancing the relevance of our experimental findings. Complement activation leads to the generation of anaphylatoxins (C3a and C5a) that attract neutrophils to the aortic wall. Once recruited neutrophils release neutrophil extracellular traps (NETs) that likely modulate the adaptive (T cell) response. Lastly, we established that CD8+ T cells are critically involved in aneurysm genesis downstream of neutrophil recruitment. Several outstanding questions remain: 1) what is the mechanism that triggers autoimmunity against a protein (fibrinogen) abundantly found in the circulation; 2) what are the events that link neutrophils and NETs to the chronic, adaptive immune (T cell) responses, and 3) how do T cells propagate the inflammatory cascade that leads to the eventual aneurysmal dilatation. We posit that a thorough investigation of the immune processes in AAA will provide new insights into mechanisms that govern aneurysm genesis and identify potential therapeutic targets for immune-based medical therapies.