Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils

Sato, Masao; Nonaka, Sakutaro; Nishimukai, Hiroaki; Nobunaga, Masashi; Kitamura, Hajime; Tomooka, Katsuhiko

doi:10.1111/j.1365-2249.1992.tb05834.x

Cited by 63 publications

(30 citation statements)

References 37 publications

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“…This hypothesis was substantiated by demonstrating that activation of human neutrophils by human MPO-ANCA or PR3-ANCA IgG releases factors that activate complement with the generation of C3a (Figure 11). These studies do not identify what factor or factors are responsible for the complement activation, but a number of candidates are suggested by the litera- ture, including reactive oxygen radicals, 24 MPO, 25 proteases, 26 and properdin. 27 Properdin is synthesized by neutrophils and stored in secondary granules that are released on activation.…”

Section: Discussionmentioning

confidence: 99%

Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies

Xiao

Schreiber

Heeringa

et al. 2007

The American Journal of Pathology

506

433

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Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAsAnti-neutrophil cytoplasmic autoantibodies (ANCA) are specific for proteins in the cytoplasm of neutrophils and monocytes. The major target antigens in patients with vasculitis and glomerulonephritis are myeloperoxidase (MPO) and proteinase 3 (PR3). ANCAs occur in greater than 80% of patients with active untreated Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune crescentic glomerulonephritis.1 There is compelling clinical and experimental evidence that ANCA IgG causes ANCA-associated vasculitis and glomerulonephritis. The strongest clinical evidence for causation is the observation that a newborn child developed glomerulonephritis and pulmonary hemorrhage shortly after delivery from a mother with MPO-ANCA-associated microscopic polyangiitis, apparently caused by transplacental transfer of ANCA IgG.2,3 Two compelling animal models of ANCA vasculitis and glomerulonephritis have been described by two different research groups.4,5 Xiao and colleagues 4 induced glomerulonephritis and systemic vasculitis by intravenous injection of either anti-MPO IgG or anti-MPO splenocytes derived from MPO knockout mice immunized with murine MPO. Induction of glomerulonephritis by anti-MPO IgG in this model is enhanced by cytokines 6 and requires neutrophils. 7 Little and colleagues 5 immunized rats with human MPO, resulting in the production of antibodies that cross reacted with rat MPO and caused vasculitis and glomerulonephritis. The pathogenic effects of these anti-MPO antibodies were augmented by cytokines.Numerous in vitro studies indicate that ANCA IgG can activate neutrophils and cause them to release proinflammatory factors. The expression of ANCA antigens (MPO and PR3) at the surface of neutrophils where they are accessible to interact with ANCA IgG is enhanced by proinflammatory cytokines, such as tu-

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Section: Discussionmentioning

confidence: 99%

Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies

Xiao

Schreiber

Heeringa

et al. 2007

The American Journal of Pathology

506

433

View full text Add to dashboard Cite

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“…[5][6][7] Here we describe a complement activation trigger distinct from serine proteases or oxidants because it was not inhibited by phenylmethylsulfonylfluoride or DPI. Moreover, this trigger is clearly present on the surface of neutrophils because it was not removed by cell washing.…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophil proteases and oxidants have been reported to activate complement in cell-free systems, [5][6][7] and supernatants of ANCA-activated neutrophils were shown to release unknown complement activating factors. 4 We investigated the ability of the neutrophil surface to activate complement and deposit active complement fragments on their plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Complement alternative pathway acts as a positive feedback amplification of neutrophil activation

Camous

Roumenina

Bigot

et al. 2011

Blood

193

196

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Complement alternative pathway plays an important, but not clearly understood, role in neutrophil-mediated diseases. We here show that neutrophils themselves activate complement when stimulated by cytokines or coagulation-derived factors. In whole blood, tumor necrosis factor/ formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate resulted in C3 fragments binding on neutrophils and monocytes, but not on T cells. Neutrophils, stimulated by tumor necrosis factor, triggered the alternative pathway on their surface in normal and C2-depleted, but not in factor B-depleted serum and on incubation with purified C3, factors B and D. This occurred independently of neutrophil proteases, oxidants, or apoptosis. Neutrophil-secreted properdin was detected on the cell surface and could focus "in situ" the alternative pathway activation. Importantly, complement, in turn, led to further activation of neutrophils, with enhanced CD11b expression and oxidative burst. Complement-induced neutrophil activation involved mostly C5a and possibly C5b-9 complexes, detected on tumor necrosis factor-and serum-acti- IntroductionNeutrophils and the complement alternative pathway (AP) are major effectors of cell-mediated and humoral innate immunity. The analysis of complement knockout mice, in experimental inflammatory diseases, shed new light on the participation of complement AP in neutrophil-mediated diseases, such as rheumatoid arthritis, 1 membranoproliferative glomerulonephritis, 2 ischemia-reperfusion injury, 3 and, more recently, antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis. 4 In an experimental model of ANCA-associated small-vessel vasculitis, the unexpected observation that factor B-deficient mice were protected from the disease, whereas C4-deficient mice were not, 4 revealed the alternative complement pathway as a new partner of this neutrophilmediated disease. It was thus reasonable to propose that neutrophils could participate in the activation of complement AP.If the activation of neutrophils by complement fragments, such as C3a or C5a, is well known, data on complement triggering by neutrophils are scarce. Neutrophil proteases and oxidants have been reported to activate complement in cell-free systems, 5-7 and supernatants of ANCA-activated neutrophils were shown to release unknown complement activating factors. 4 We investigated the ability of the neutrophil surface to activate complement and deposit active complement fragments on their plasma membrane.Complement activation on blood cells is kept under control by fluid phase regulators (ie, plasma factor H and C4b-binding protein) and by cell membrane regulators (ie, decay accelerating factor DAF [CD55] and membrane cofactor protein MCP [CD46]). These regulators prevent the formation and accelerate the decay of C3bBb and C4b2a alternative and classic C3-convertases and act as cofactors for factor I-mediated C3b and C4b proteolysis. Neutrophils also express CR1 (CD35), which is the only cofactor allowing factor I to fully degrade ...

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“…5 This is reminiscent of previous data showing that H 2 O 2 and neutrophil-derived oxidants trigger the complement AP and may also activate C5 directly. 33 Circulating free heme concentrations are about 6 to 30 mM in sickle-cell disease and thalassemia 7 but have not been reported in aHUS. Mechanical hemolysis in the renal microvasculature in Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Frimat

Tabarin

Dimitrov

et al. 2013

Blood

217

248

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Key Points• Heme activates complement alternative pathway in serum and on endothelial cell surfaces.• Heme-induced complement activation in the presence of complement mutations contributes as a secondary hit to the development of aHUS.Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis, and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for disease manifestation. We investigated whether hemolysis-derived heme contributes to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a, and sC5b9. We demonstrated that hemeexposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes, and promoted formation of an overactive C3/C5 convertase. Heme induced decreased membrane cofactor protein (MCP) and decay-accelerating factor (DAF) expression on endothelial cells, giving Factor H (FH) a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel-Palade bodies, with membrane expression of P-selectin known to bind C3b and trigger the AP, and the release of the prothrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS. (Blood. 2013;122(2):282-292) IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare kidneypredominant thrombotic microangiopathy (TMA) associated with formation of fibrin-platelet clots in the glomerular microvasculature leading to mechanical hemolysis. 1 This disease is related to a dysregulation of the complement alternative pathway (AP), as shown by the identification of genetic or acquired abnormalities in AP regulators or activators in more than 60% of patients. 2 aHUS has an incomplete penetrance among mutation carriers, and a triggering event is presumably required for the disease manifestation. This primary hit can be an infection, pregnancy, drug, or other cell-activating event. Sera from aHUS patients carrying mutations deposit complement on endothelial cells activated by inflammatory cytokines, 3 suggesting continuous aggression on the endothelium. However, not all infections trigger aHUS in patients. It is frequently the second pregnancy postpartum period that is associated with the disease.4 Therefore, other factors appear to be necessary to exceed the threshold of tolerable endothelial stress leading to severe TMA lesions.In acute phase TMA, mechanical hemolysis induces the release of hemoglobin into the bloodstream. 5 This hemoglobin is readily oxidized to ferric hemoglobin (methemoglobin) which, in turn, liberates heme. In physiological conditions...

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Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils

Cited by 63 publications

References 37 publications

Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies

Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies

Complement alternative pathway acts as a positive feedback amplification of neutrophil activation

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

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