Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm.
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, properdin-free 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 properdin-targeting strategies may halt aneurysmal growth.
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Hui-Fang
HF
Zhou
Huimin
H
Yan
Cordula M
CM
Stover
Tamara Montes
TM
Fernandez
Santiago
S
Rodriguez de Cordoba
Wen-Chao
WC
Song
Xiaobo
X
Wu
Robert W
RW
Thompson
Wilhelm J
WJ
Schwaeble
John P
JP
Atkinson
Dennis E
DE
Hourcade
Christine T N
CT
Pham
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D003167:Complement Activation / Q000187:drug effects; D003165:Complement System Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D011414:Properdin / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D011414:Properdin; D003165:Complement System Proteins