Properdin: Emerging Roles of a Pattern-Recognition Molecule

Kemper, Claudia; Atkinson, John P.; Hourcade, Dennis E.

doi:10.1146/annurev-immunol-030409-101250

Cited by 202 publications

(195 citation statements)

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“…These findings suggest that IFN-γ-producing NKT cells reduce CD55 expression on neutrophils by regulating IL-10 production in CLP-induced sepsis. CD55 inhibits complement convertase activity by dissociating Bb factor from convertase attached to cell membranes [27]. Minimal Bb factor expression was detected in CD1d-deficient peritoneal cells, whereas high expression of Bb factor was found in WT peritoneal cells during CLP-induced sepsis (Fig.…”

mentioning

confidence: 93%

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Kim

Ahn

et al. 2014

Eur J Immunol

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A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-γ, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d −/− mice, while the mortality rate was lower in CD1d −/− mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d −/− mice. As assessed by intracellular staining, NKT cells expressed IFN-γ, while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production by WT, but not IFN-γR-deficient, neutrophils. Meanwhile, CD1d −/− mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d −/− mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-γ-deficient, NKT cells into CD1d −/− mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-γ-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis.Keywords: C5a r IFN-γ r Neutrophils r NKT cell r Sepsis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNKT cells are a distinct T-cell subset characterized by the expression of natural killer receptors and semi-invariant TCRs. These cells recognize glycolipids presented by CD1d, an MHC class I-like Correspondence: Dr. Doo Hyun Chung e-mail: doohyun@snu.ac.kr protein expressed by APCs [1]. During bacterial infection, TCRs on NKT cells directly recognize glycolipids derived from certain Gramnegative bacterial membranes [2,3] and can be activated by innate cytokines secreted by dendritic cells that have been activated by microorganisms [2,4]. Furthermore, LPS-mediated engagement of TLR4 directly activates NKT cells in terms of differential * These authors contributed equally to this work. Eur. J. Immunol. 2014Immunol. . 44: 2025Immunol. -2035 cytokine production, thereby regulating immune diseases [5]. These findings suggest that NKT cells, activated during immune responses against bacteria, regulate bacteria-mediated pathologic processes such as sepsis. Sepsis is a complex inflammatory dysregulation that causes multiple organ dysfunction and coagulopathy, often resulting in death [6,7]. Several studies have demonstrated that NKT cells promote LPS-or cecal ligation and puncture (CLP)-induced sepsis in mice through the production of . Consistent with these findings, two independent studies have demonstrated that treatment of C57BL/6 mice with anti-CD1d antibody enhances survival rates during CLP-induced sepsis [11,12], suggesting that NKT-cell-mediated promotion of sepsis depends on an interaction between CD1d and TCR...

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confidence: 93%

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Kim

Ahn

et al. 2014

Eur J Immunol

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“…These claims were controversial, and properdin-dependent complement activation was dismissed by the scientific community (2-4); however, the "properdin system" was reborn as the alternative pathway (AP) more than 20 y later (3), with properdin described as a stabilizer and positive regulator of the AP C3 convertase (5,6). Properdin and its possible different roles in complement activation have been a basis for further studies in this area (7)(8)(9)(10)(11).…”

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confidence: 99%

Properdin binding to complement activating surfaces depends on initial C3b deposition

Harboe

Johnson

Nymo

et al. 2017

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

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Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

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“…This seems to be supported by the reports on the growing role of properdin (FP) as a recognition pattern molecule, which can activate AP by binding to C3b. Also, C3 and C5 can be directly activated by 'extrinsic' proteases that are not traditionally associated with the complement system, for example, thrombin and plasmin [16,17]. The CP is triggered by IgG and or IgM-containing immune complexes, viruses and acute-phase proteins, binding to C1q.…”

Section: C3 Functionmentioning

confidence: 99%

“…In case of nucleated cells, it induces activation of inflammatory response and tissue damage (Fig. 2) [1,6,15,[17][18][19][20][21][22][23][24][25].…”

Section: C3 Functionmentioning

confidence: 99%

“…In an acute-phase reaction, in response to proinflammatory agents, including interleukin 1 (IL-1) or IL-6, tumor necrosis factor-α, interferon-γ, and lipopolysaccharide, 2-to 3-fold increase in C3 concentration may be observed [12]. Moreover, recent studies have established that fluid phase C3b or C3(H 2 O) may be recruited by FP bound to the necrotic and apoptotic human cells, acting as a pattern recognition molecule [17,18].…”

Section: C3 Functionmentioning

confidence: 99%

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The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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Properdin: Emerging Roles of a Pattern-Recognition Molecule

Cited by 202 publications

References 123 publications

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Properdin binding to complement activating surfaces depends on initial C3b deposition

The role of the alternative pathway of complement activation in glomerular diseases

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