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.