Role of Complement Cascade in Abdominal Aortic Aneurysms

Hinterseher, Irene; Erdman, Robert; Donoso, Larry A.; Vrabec, Tamara R.; Schworer, Charles M.; Lillvis, John H.; Boddy, Amy M.; Derr, Kimberly; Golden, Alicia; Bowen, W. Don; Gatalica, Zoran; Tapinos, Nikos; Elmore, James R.; Franklin, David P.; Gray, John; Garvin, Robert P.; Gerhard, Glenn S.; Carey, David J.; Tromp, Gerard; Kuivaniemi, Helena

doi:10.1161/atvbaha.111.227652

Cited by 48 publications

(58 citation statements)

References 38 publications

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“…Alternatively, the prominent contribution of the AP in our model system may be explained by the fact that we focused on the early initiating events of aneurysm development, whereas the human tissue samples were obtained at late-stage disease. In contrast to our results, the study by Hinterseher et al (30) did not detect the presence of factor B in the AAA tissue samples (30,32). This discrepancy could possibly result from the different detection antibodies used.…”

Section: Discussioncontrasting

confidence: 99%

“…Age-related macular degeneration, aHUS, and dense deposit disease (membranoproliferative glomerulonephritis type II) are caused by dysregulation of the AP and associated with alleles that encode impaired forms of the AP regulator proteins factor H, factor I, and CD46 or gain of function forms of the AP convertase components fB and C3 (13). This finding does not seem to be the major cause of AAA, because in the works by both Hinterseher et al (30) and Bradley et al (32), consistent associations between AAA disease and AP genetic polymorphisms were not found (30,32). Instead, we found that antibody binding to the injured aortic wall (in this case, damaged by elastase perfusion) leads to complement activation, thereby initiating the inflammatory cascade that eventually culminates in AAA formation.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, Hinterseher et al (30) conducted a genome-wide microarray expression profile of human AAA tissue samples vs. normal tissue and found increased expression of the genes encoding the CP/LP protein C2 and the CP protein C1 (C1qA and C1qC) as well as the anaphylatoxin receptors C3aR and C5aR (30). Moreover, the work by Hinterseher et al (30) also showed increased C2 in the disease tissue.…”

Section: Discussionmentioning

confidence: 99%

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Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

Zhou

Yan

Stover

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a complex inflammatory vascular disease. There are currently limited treatment options for AAA when surgery is inapplicable. Therefore, insights into molecular mechanisms underlying AAA pathogenesis may reveal therapeutic targets that could be manipulated pharmacologically or biologically to halt disease progression. Using an elastase-induced AAA mouse model, we previously established that the complement alternative pathway (AP) plays a critical role in the development of AAA. However, the mechanism by which complement AP is initiated remains undefined. The complement protein properdin, traditionally viewed as a positive regulator of the AP, may also initiate complement activation by binding directly to target surfaces. In this study, we sought to determine whether properdin serves as a focal point for the initiation of the AP complement activation in AAA. Using a properdin loss of function mutation in mice and a mutant form of the complement factor B protein that produces a stable, properdinfree AP C3 convertase, we show that properdin is required for the development of elastase-induced AAA in its primary role as a convertase stabilizer. Unexpectedly, we find that, in AAA, natural IgG antibodies direct AP-mediated complement activation. The absence of IgG abrogates C3 deposition in elastase-perfused aortic wall and protects animals from AAA development. We also determine that blockade of properdin activity prevents aneurysm formation. These results indicate that an innate immune response to self-antigens activates the complement system and initiates the inflammatory cascade in AAA. Moreover, the study suggests that properdintargeting strategies may halt aneurysmal growth.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

Zhou

Yan

Stover

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent study showed that C2, an essential component of both the CP and the LP, is abundantly deposited in AAA tissues (25). However, based on increased expression of C1q protein, the investigators concluded that the CP, not the LP, plays a more prominent role in human AAA.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple studies have implicated the complement cascade in the pathogenesis of human AAA (10,25,26). Evidence so far implicates both CP and AP; however, the role of the LP has not been explored.…”

Section: G10 Mab Binds Mannan-binding Lectin and Initiates The Complementioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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 elastaseperfused 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.A bdominal aortic aneurysm (AAA) is a common vascular disorder that affects ∼5% of men and ∼1.5% of women ages 65 and older (1, 2). Rupture of AAA presents a medical emergency that accounts for 15,000 deaths annually in the United States (3). Currently, surgical repair represents the only treatment option for large AAAs, whereas surgery in small AAAs offers no clear overall long-term survival advantage (4, 5). Thus, medical management, to inhibit or reverse the progression of small AAAs, has received increasing attention. Major challenges remain in the development of therapeutic agents that impede aneurysm expansion, as our understanding of the pathophysiology underlying this disease is incomplete.One of the defining characteristics of AAA is inflammation accompanied by a cellular infiltrate that is predominantly lymphocytic (6-8). The elastase-induced AAA mouse model recapitulates many key features of human AAA, including the inflammatory response (9). We previously established with this model that aneurysm development requires factor B and properdin of the complement alternative pathway (AP) (10, 11). We showed that mice deficient in B cells (and hence antibodies), called μMT mice, are protected against aneurysm formation. Reconstitution with natural IgG, but not IgM, from wild-type mice res...

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