Division of Rheumatology, Department of Medicine, and Division of Vascular Surgery, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63124.
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4335-44. doi: 10.1073/pnas.1315512110. Epub 2013 Oct 28.
Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastase-perfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.
腹主动脉瘤 (AAA) 是一种常见的血管疾病，由于其进行性增大并最终破裂，导致死亡率较高。目前尚无已知的治疗方法可以改变动脉瘤扩张的速度。因此，了解引发和维持动脉瘤生长的过程对于开发旨在阻止疾病进展的医学治疗方法至关重要。我们之前使用弹性蛋白酶诱导的 AAA 小鼠模型，该模型重现了人类 AAA 的关键特征，报告称一种天然 IgG 抗体可定向补体替代途径激活，并引发导致动脉瘤形成的炎症过程。然而，这种天然抗体的靶标尚不清楚。在此，我们鉴定出一种天然 IgG，它可结合弹性蛋白酶灌注主动脉组织中沉积的纤维蛋白原，激活补体凝集素途径 (LP)，并诱导 AAA。此外，我们确定该抗体糖基化模式的改变严重影响其在体内激活 LP 的能力。我们发现 LP 激活先于替代途径，并且缺乏 LP 补体蛋白甘露聚糖结合凝集素可消除弹性蛋白酶诱导的 AAA。在人类 AAA 组织中，鼠抗纤维蛋白原抗体识别的表位与甘露聚糖结合凝集素染色阳性的区域相同，这表明 LP 在人类中也被激活。最后，我们证明在一部分 AAA 患者的循环抗体中，针对纤维蛋白原或人类动脉瘤组织中纤维蛋白原相关表位发生反应。我们的研究结果支持这样一种观点，即针对主动脉壁自身抗原的自身免疫过程可能在 AAA 的免疫发病机制中起核心作用。
