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

Abstract

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.

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

“…A key step in aneurysmal development in the mouse model occurs when pathogenic natural IgG antibodies bind to antigens exposed or unmasked by elastase perfusion and form immune complexes (ICs) that mediate complement activation (11). To capture these ICs, we perfused WT mice with elastase, then harvested the aortas immediately after perfusion (T0) or at 30 min (T30).…”

“…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 restores susceptibility to the elastase-induced AAA phenotype (11). These results suggest that mouse IgG recognizes a self-antigen that is revealed following elastase perfusion and the antibody-antigen complex activates complement in the initiation of the inflammatory cascade (10,11).…”

“…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 restores susceptibility to the elastase-induced AAA phenotype (11). These results suggest that mouse IgG recognizes a self-antigen that is revealed following elastase perfusion and the antibody-antigen complex activates complement in the initiation of the inflammatory cascade (10,11). Congruent with our findings in the animal model, previous studies of human AAA tissues revealed the presence of B cells and IgG antibodies sometimes seen in organized follicle-like structures, raising the question that AAA is the result of a dysregulated autoimmune response against putative aortic wall self-antigens (7,(12)(13)(14)(15).…”

Unexpected Role for Properdin in Complement C3 Glomerulopathies

“…On the other hand one should be aware of the finding by Kimura et al 12 and Zhou et al 13 that the absence of fP protects against complement-mediated tissue injury in diseases such as complement-mediated embryonic lethality, experimental collagen arthritis, and abdominal aortic aneurysm.…”