The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis

Kemper, Claudia; Mitchell, Lynne M.; Zhang, Lijuan; Hourcade, Dennis E.

doi:10.1073/pnas.0801015105

Cited by 141 publications

(196 citation statements)

References 45 publications

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“…The observation that properdin was present on anti-CCP antibodies in the in vitro model is interesting in view of recent reports describing properdin as a recognition molecule, like C1q and MBL, in addition to its role as a stabilizing factor of the alternative pathway C3 convertase (30,(42)(43)(44). Although our data clearly indicate the involvement of properdin and thus the alternative pathway, they do not discriminate between the role of properdin as a recognition molecule and its role as part of the stabilized alternative pathway C3 convertase.…”

Section: Discussionmentioning

confidence: 86%

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

218

149

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Objective. It has been suggested that anticitrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.Methods. We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement.Results. Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.Conclusion. Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

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Section: Discussionmentioning

confidence: 86%

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

218

149

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“…Properdin is in the plasma and also stored in neutrophil granules, where it is rapidly released during cell stimulation (15,19). To determine whether locally secreted properdin (derived from infiltrating neutrophils) can drive the AAA phenotype, we reconstituted fP −/o mice with purified bone marrow-derived neutrophils using a regimen that we had previously used to successfully restore AAA phenotype in the dipeptidyl peptidase I-deficient mice (18).…”

Section: Resultsmentioning

confidence: 99%

“…More recently, evidence has emerged that properdin may act as an initiator of the AP, binding directly to target cell surfaces and providing a platform for the AP C3 convertase assembly (15,16). We previously obtained compelling histochemical evidence for the presence of properdin on the luminal surface of human AAA specimens (12), and this finding led us to hypothesize that properdin may serve as a focal point for the initiation of the AP in AAA.…”

mentioning

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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“…Encouraged by these findings, we investigated the use of recombinant P n as a bactericidal agent under in vitro and in vivo conditions. Kemper et al (40) postulated that properdin can even act as a pattern recognition molecule, binding to pathogen surfaces and to apoptotic and necrotic cells, where it initiates the formation of alternative pathway convertases. The molecular events that would allow properdin to specifically discriminate between activating and nonactivating surfaces remain unclear, however.…”

Section: Discussionmentioning

confidence: 99%

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

Ali

Hayat

Saeed

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (P n ), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of P n (100 μg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the P n treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of P n treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of P n at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the salinetreated control group (P < 0.0001). Our findings show a significant therapeutic benefit of P n administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.

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The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis

Cited by 141 publications

References 45 publications

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

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

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

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