The role of antibody in the activation of the alternative complement pathway

Ratnoff, William D.; Fearon, Douglas T.; Austen, K. Frank

doi:10.1007/bf02116280

Cited by 93 publications

(55 citation statements)

References 51 publications

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“…Antibody:antigen reactions can direct AP activity independently of the CP or LP (the antibody-dependent AP) (24)(25)(26). In particular, antibodies bound to self-tissue can provide sites for C3 deposition that are protected from the inhibitory activities of the complement regulators and thus, confer AP-activating capacity.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Thus, blocking of the alternative pathway was efficient in augmenting killing as was blocking of the classical pathway, and factor D, but not C1q, could reconstitute the killing potential of C1q/factor Ddepleted immune serum. The alternative pathway could be activated through amplification of the classical pathway or through direct activation by the protective Ab [31,32]. A direct activation by the Ab is not unlikely since it is known that both the Fc and Fab fragments of human IgG contain regions that are vulnerable to nucleophilic attack by C3b [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…The alternative pathway could be activated through amplification of the classical pathway or through direct activation by the protective Ab [31,32]. A direct activation by the Ab is not unlikely since it is known that both the Fc and Fab fragments of human IgG contain regions that are vulnerable to nucleophilic attack by C3b [32,33].…”

Section: Discussionmentioning

confidence: 99%

Critical role for complement receptor 3 (CD11b/CD18), but not for Fc receptors, in killing of Streptococcus pyogenes by neutrophils in human immune serum

et al. 2005

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During phagocytosis, surface receptors on neutrophils interact with pathogens opsonized with complement factor C3b/iC3b and in some cases with antibodies. In human immune sera antibodies directed against surface‐bound M proteins mediated killing of Streptococcus pyogenes by neutrophils. Surprisingly, blocking of the Fc receptors had little effect on the killing. In contrast, inhibition of C3b/iC3b generation, or blocking of the major neutrophil iC3b receptor CD11b/CD18, enabled S. pyogenes to grow efficiently in immune sera. Inhibition of CD11b/CD18, but not of CD32, the major neutrophil signaling Fc receptor, prevented Streptococcus‐induced NADPH oxidase‐dependent respiratory burst, and blocking of C3b/iC3b formation inhibited Streptococcus‐induced activation of Cdc42, a small GTPase critically involved in transmitting pro‐inflammatory signals to the cytoskeleton. Consequently, ligation of CD11b/CD18 by bacteria‐bound iC3b is necessary for inducing a neutrophil response leading to elimination of S. pyogenes in immune human serum.

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“…An "activating" surface is, in large part, one without adequate regulatory protein function to control alternative pathway activation (22) or one that is not favorable to control of the alternative pathway by factor H (23). Congenital or acquired deficiency of the complement regulatory proteins can result from Abs that block endogenous regulatory mechanisms (24) or decreased expression of complement regulatory proteins (25,26). Diminished function of these regulatory proteins has been identified as a cause of several of the diseases discussed below.…”

Section: Continous Active Control Of Alternative Pathway Activation Imentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

391

350

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The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

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The role of antibody in the activation of the alternative complement pathway

Cited by 93 publications

References 51 publications

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

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

Critical role for complement receptor 3 (CD11b/CD18), but not for Fc receptors, in killing of Streptococcus pyogenes by neutrophils in human immune serum

The Central Role of the Alternative Complement Pathway in Human Disease

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