Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro

Weidner, Sven; Neupert, Werner; Goppelt‐Struebe, Margarete; Rupprecht, Harald

doi:10.1002/1529-0131(200107)44:7<1698::aid-art294>3.0.co;2-j

Cited by 81 publications

(52 citation statements)

References 35 publications

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“…antigens, [29][30][31] are activated by ANCA, and are consistently detected in ANCA-induced NCGN, their role is less well understood. 31,32 In addition, although ANCA-induced neutrophil and monocyte activation has been extensively characterized in vitro, the effector mechanisms that actually cause the in vivo damage are not yet characterized. It is hypothesized that in a cytokine-rich milieu, ANCAs bind to cell surface membrane-expressed antigens on neutrophils and monocytes, leading to cellular activation and adhesion to the endothelium, the generation of reactive oxygen species, and the release of proteases and other toxic granule proteins, the cumulative effects of which result in small-vessel vasculitis, including NCGN.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis

Schreiber

Pham

et al. 2012

Journal of the American Society of Nephrology

109

119

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The pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic GN (NCGN) is incompletely understood. Dipeptidyl peptidase I (DPPI) is a cysteine protease required for the activation of neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase, and proteinase 3, which are enzymes that modulate inflammation. We used a mouse model of anti-myeloperoxidase (MPO) antibodyinduced NCGN to determine whether active NSPs contribute to its pathogenesis. MPO-deficient animals immunized with murine MPO, irradiated, and transplanted with wild-type bone marrow developed NCGN. In contrast, transplantation with bone marrow that lacked DPPI or lacked both neutrophil elastase and proteinase 3 protected mice from NCGN induced by anti-MPO antibody. The kidneys of mice reconstituted with DPPI-deficient bone marrow generated significantly less IL-1b than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1b in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1b was NSP dependent; exogenous addition of PR3 restored IL-b production in DPPI-deficient monocytes. Last, the IL-1 receptor antagonist anakinra protected animals against anti-MPO antibody-induced NCGN (16.7%66.0% versus 2.4%61.7% crescents), suggesting that IL-1b is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1b generation and that these processes may provide therapeutic targets for ANCAmediated diseases in humans.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis

Schreiber

Pham

et al. 2012

Journal of the American Society of Nephrology

109

119

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“…Furthermore, production of oxygen radicals by TNF-α-primed monocytes in response to MPO or PR3-ANCA has been described (13). In addition to a pathogenic role for ANCA, cellular immunity is also considered to be important in ANCA vasculitis, with a role for effector CD4 + cells demonstrated in a murine model (14).…”

Section: Introductionmentioning

confidence: 99%

Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development

Popat¹,

Hakki²,

Thakker³

et al. 2017

JCI Insight

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“…3,4 At first, ANCAs were regarded only as clinical markers of disease activity, but it is now apparent that they have direct biologic effects on neutrophils 5,6 and monocytes. 7 The binding of ANCAs to antigen expressed on the leukocyte cell surface following cytokine priming is followed by the activation of an array of intracellular signaling pathways, 8 with resultant degranulation and dysregulated apoptosis. 9 Granulocyte infiltration and fibrinoid necrosis of the vessel wall are the pathologic hallmarks of SVV.…”

Section: Introductionmentioning

confidence: 99%

Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo

Little

Smyth

Yadav

et al. 2005

Blood

246

190

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Systemic small vessel vasculitis is associated with antineutrophil cytoplasm antibodies (ANCAs). While there is mounting in vitro evidence to suggest that ANCAs are capable of enhancing leukocyte-endothelial interactions, no in vivo evidence for this has been provided. In this study a novel rat model of ANCA-associated experimental autoimmune vasculitis (EAV), induced by immunization with human myeloperoxidase (MPO), was used to analyze directly the potential effect of ANCAs on leukocyte-venular wall interactions in vivo as observed by intravital microscopy. These rats developed anti-MPO antibodies directed against rat leukocytes, showed pathologic evidence of small vessel vasculitis, and had enhanced leukocyte adhesion and transmigration in response to the chemokine Gro␣ ( IntroductionSystemic small vessel vasculitis (SVV) results in rapidly progressive glomerulonephritis and lung hemorrhage in humans and is usually fatal if untreated. 1 It is characterized by microvascular inflammation and necrosis in a variety of organs. The 2 organs that are most extensively injured in this manner are the kidney, through the development of pauci-immune crescentic glomerulonephritis, and the lung, with consequent alveolar hemorrhage. The association between antineutrophil cytoplasm antibodies (ANCAs) and SVV, initially described in the 1980s, 2 has attracted considerable interest over the past decade. These autoantibodies are principally directed against myeloperoxidase (MPO) and proteinase-3. 3,4 At first, ANCAs were regarded only as clinical markers of disease activity, but it is now apparent that they have direct biologic effects on neutrophils 5,6 and monocytes. 7 The binding of ANCAs to antigen expressed on the leukocyte cell surface following cytokine priming is followed by the activation of an array of intracellular signaling pathways, 8 with resultant degranulation and dysregulated apoptosis. 9 Granulocyte infiltration and fibrinoid necrosis of the vessel wall are the pathologic hallmarks of SVV. For this reason, investigative efforts have focused on the influence that ANCAs have on the interaction between leukocytes and the vascular endothelium, specifically with reference to the inflammatory cascade of leukocyte rolling, adhesion, and transmigration. In this context, in vitro studies using flow chamber models have shown that ANCAs can cause rolling neutrophils to arrest on platelet monolayers 10 and to promote firm adhesion and migration of rolling neutrophils on endothelial cells. 11,12 Despite growing in vitro evidence implicating ANCAs as an inducer of leukocyte-endothelial cell interactions, there has been no evidence to date demonstrating such an effect of these antibodies in vivo. The ability of ANCAs to induce systemic small vessel vasculitis and crescentic glomerulonephritis, however, has been demonstrated by transfer of anti-MPO antibodies in a mouse model of vasculitis. 13 Crescent formation in these animals occurred secondary to fibrinoid necrosis of the glomerular tuft, which was induced by necrosis and...

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Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro

Cited by 81 publications

References 35 publications

Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis

Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis

Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development

Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo

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