Immune-mediated pathways in pathogenesis of abdominal aortic aneurysm

描述(由申请人提供)： 这项建议的长期目标是阐明腹主动脉瘤(AAA)形成和发展的病理生理机制。AAA是一种常见的、可能致命的血管疾病，65岁及以上个体中高达9%的患者会受到影响。AAA是一种与男性性别、高血压、动脉粥样硬化、冠状动脉疾病和吸烟有关的复杂疾病。它是美国前二十大死因之一，每年造成约15,000人死亡。据估计，每20名50岁以上的美国退伍军人中就有1人患有AAA。AAA的治疗选择目前仅限于手术干预。开放手术修补大型腹主动脉(直径大于5.5厘米)是预防破裂死亡的有效选择。开放手术修复虽然有效，但术后死亡率较高(高达6%)。鉴于治疗选择有限，AAA患者的高龄--这可能会阻止他们接受手术--因此，通过药物治疗来减缓病情进展是一个有吸引力的选择。这一应用的目的是为了进一步了解AAA中涉及的免疫介导的途径。越来越多的证据表明，AAA是一种炎症性、免疫介导性疾病。利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，我们先前证实，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针对纤维蛋白原的致病免疫球蛋白自身抗体，该抗体与弹性酶灌流的小鼠主动脉壁组织结合，激活 补体凝集素途径(LP)位于替代途径(AP)的上游，并诱导AAA的形成。此外，我们还证明，在人类AAA组织中，纤维蛋白原与甘露聚糖结合凝集素(MBL)共定位，甘露聚糖结合凝集素(MBL)是LP的重要组成部分，这表明对纤维蛋白原的识别也可能启动人类补体的激活。此外，我们还发现，部分AAA患者的循环自身抗体对提纯的纤维蛋白原起反应。 在人类动脉瘤组织中的体外和纤维蛋白原相关表位，进一步增强了我们的实验结果的相关性。补体激活导致产生过敏性毒素(C3a和C5a)，将中性粒细胞吸引到主动脉壁。一旦被招募，中性粒细胞就会释放可能调节适应性(T细胞)反应的中性粒细胞胞外陷阱(Net)。最后，我们证实CD8+T细胞在中性粒细胞募集后下游动脉瘤的形成中起关键作用。我们认为，对AAA免疫过程的彻底研究将为控制动脉瘤发生的机制提供新的见解，并为基于免疫的医学治疗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.