Complement amplification revisited

Lutz, Hans; Jelezarova, Emiliana

doi:10.1016/j.molimm.2005.06.020

Cited by 73 publications

(69 citation statements)

References 97 publications

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“…The studies herein establish that antibodymediated LP activation is essential in the pathogenesis of elastaseinduced AAA. Although the role of antibody in complement AP activation/amplification has been studied (40,41), and reports indicate that adherent immune complexes can induce AP activation in vivo (42,43), direct antibody-mediated activation of the AP in elastase-induced AAA was not demonstrated (11). Instead, the results herein are consistent with our previous findings that properdin of the AP does not initiate C3 convertase assembly but serves mainly as a convertase stabilizer (11).…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…In its dimeric form (C3bC3bIgG), it is seven to 10 times more efficient in generating a C3 convertase than surface-bound monomeric C3b. 71 The very same enzyme on surfaces or on IgG in the fluid phase becomes a C5 convertase by acquiring an additional C3b in its vicinity, which increases the affinity of the enzyme for C5. Here we show in red just one of the possible amplification routes, which seems to be the most relevant in DDD (see text).…”

Section: Animal Studies and Dddmentioning

confidence: 99%

New Approaches to the Treatment of Dense Deposit Disease

Smith¹,

Alexander

Barlow

et al. 2007

Journal of the American Society of Nephrology

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233

201

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“…In the absence of a cofactor, factor B is recruited, resulting in the formation of the C3 convertase and proceeding of complement activation. 28 Since factor H co-immunoprecipitated with both, AAVC3b complexes and with AAV alone, it is likely that iC3b is generated on the viral capsid, a possible mechanism used by AAV to limit the innate response. 27 Many pathogens have evolved mechanisms to evade direct activation of the complement system by mimicking host surfaces, thereby recruiting factor H. 29 Consistent with these findings, AAV vectors fail to activate the alternative pathway of complement.…”

Section: Innate Immunitymentioning

confidence: 99%