Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation

Xu, Wei; Berger, Stefan; Trouw, Leendert A.; Boer, Helen de; Schlagwein, Nicole; Mutsaers, Chantal A.; Daha, Mohamed R.; Kooten, Cees van

doi:10.1016/j.molimm.2008.08.130

Cited by 32 publications

(61 citation statements)

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“…Indeed, monocyte incubation with C1qD reconstituted with C1q, factor P, and factor D shows similar levels of apoptotic cell uptake to those seen with cells incubated in the presence of 10% NHS (Fig. 5 B ), supporting a contribution of alternative complement pathway components and/or a direct effect of properdin/factor P on apoptotic cell uptake by these cells, as has been reported previously (51, 52). Opsonization with iC3b has previously been shown to enhance uptake of apoptotic cells by human but not murine iDCs (53, 54).…”

Section: Discussionsupporting

confidence: 86%

C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells

Fraser¹,

Laust²,

Nelson

et al. 2009

The Journal of Immunology

143

151

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C1q, the first component of the classical complement pathway, is also a pattern recognition receptor involved in the recognition and clearance of apoptotic cells. C1q deficiency in humans leads to development of lupus-like autoimmune disease, and it has been speculated that impaired clearance of apoptotic cells may contribute to disease development. Since phagocytes initiate specific and appropriate immune responses as a result of initial ligand-receptor interactions, regulation of gene expression by C1q may also contribute to the sculpting of an immune response to the ingested “self-Ags.” In this study, the role of C1q in apoptotic cell clearance and subsequent modulation of cytokine release by phagocytes was assessed including donor matched human monocytes, monocyte-derived macrophages (HMDMs), and dendritic cells (DCs). First, C1q binding is much greater to late compared with early apoptotic cells. Second, C1q binding to apoptotic cells significantly enhanced the levels of ingestion by monocytes but had no effect on HMDM and DC uptake. Third, in the presence of serum, C1q bound to apoptotic cells, activated the complement pathway, leading to C3b deposition, and enhancement of uptake of apoptotic cells by monocytes, HMDMs, and DCs. Finally, although C1q, either immobilized on a plate or bound to apoptotic cells, modulates the LPS-induced cytokine levels released by human monocytes, HMDMs, and DCs toward a more limited immune response, both the degree and direction of modulation differed significantly depending on the differentiation state of the phagocyte, providing further evidence of the integration of these cell- and environment-specific signals in determining appropriate immune responses.

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Section: Discussionsupporting

confidence: 86%

C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells

Fraser¹,

Laust²,

Nelson

et al. 2009

The Journal of Immunology

143

151

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“…Additionally, we found that purified properdin as well as properdin from plasma bound in a dose-dependent fashion to P-S CpG. Recent advances in complement biology indicate that properdin not only stabilizes the AP convertase but also binds directly to targets such as necrotic cells, pathogens, and DNA (41, 42). The proposed model postulates that properdin binds noncovalently to target surfaces, thereby recruiting C3b and allowing for AP convertase build-up (42, 43).…”

Section: Discussionmentioning

confidence: 87%

Complement Activation by CpG in a Human Whole Blood Loop System: Mechanisms and Immunomodulatory Effects

Mangsbo

Sánchez

Anger

et al. 2009

The Journal of Immunology

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Phosphorothioate oligodeoxynucleotides can activate complement, and experimental murine studies have revealed differential effects upon simultaneous TLR stimulation and complement activation compared with either event alone. We set out to investigate the immune stimulatory effects of CpG 2006 in fresh non-anticoagulated human blood with or without presence of active complement. We also sought to elucidate the mechanism behind complement activation upon stimulation with phosphorothioate CpG 2006. In a human blood loop system, both backbone and sequence-specific effects by CpG were counteracted by selective inhibition of C3. Furthermore, DNA backbone-mediated CD40 and CD83 expression on monocytes and sequence-specific IL-6 and TNF production were reduced by complement inhibition. CpG-induced complement activation occurred via either the classical or the alternative pathway and deposits of both IgM and properdin, two activators of complement, were detected on CpG after incubation with EDTA plasma. Quartz crystal microbalance with dissipation monitoring demonstrated alternative pathway convertase build-up onto CpG as a likely pathway to initiate and sustain complement activation. Specific inhibition of C3 suppressed CpG 2006 uptake into monocytes indicating that C3 fragments are involved in CpG internalization. The interplay between complement and TLR9 signaling demonstrated herein warrants further investigation.

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“…Properdin, first identified in 1959 (Lepow et al, 1959) and known to be a stabilizer of the central enzyme in alternative pathway amplification (Muller-Eberhard, 1988), was recently proposed to be a pattern recognition molecule with the ability to initiate complement activation (Kemper et al, 2008; Kemper et al, 2009; Spitzer et al, 2007; Xu et al, 2008; Agarwal et al, 2010). The physiological forms of properdin have been recently shown to be more selective in their recognition than originally proposed (Ferreira et al, 2010).…”

Section: Recognition Molecules Used By the Alternative Pathway To mentioning

confidence: 99%

Complement control protein factor H: The good, the bad, and the inadequate

Ferreira

Pangburn

Cortés

2010

Molecular Immunology

370

357

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The complement system is an essential component of the innate immune system that participates in elimination of pathogens and altered host cells and comprises an essential link between the innate and adaptive immune system. Soluble and membrane-bound complement regulators protect cells and tissues from unintended complement-mediated injury. Complement factor H is a soluble complement regulator essential for controlling the alternative pathway in blood and on cell surfaces. Normal recognition of self cell markers (i.e. polyanions) and C3b/C3d fragments is necessary for factor H function. Inadequate recognition of host cell surfaces by factor H due to mutations and polymorphisms have been associated with complement-mediated tissue damage and disease. On the other hand, unwanted recognition of pathogens and altered self cells (i.e. cancer) by factor H is used as an immune evasion strategy. This review will focus on the current knowledge related to these versatile recognition properties of factor H.

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Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation

Cited by 32 publications

References 0 publications

C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells

C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells

Complement Activation by CpG in a Human Whole Blood Loop System: Mechanisms and Immunomodulatory Effects

Complement control protein factor H: The good, the bad, and the inadequate

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