How anti-neutrophil cytoplasmic autoantibodies activate neutrophils

Kettritz, Ralph

doi:10.1111/j.1365-2249.2012.04615.x

Cited by 92 publications

(70 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Numerous in vitro studies established an ANCA-mediated robust Phox-dependent respiratory burst in neutrophils and although less well studied, monocytes. 2,[11][12][13][14]38,39 Together with the fact that ROS modify and damage proteins and lipids, ANCA-induced ROS release is considered a key pathogenic component for necrotizing small vessel vasculitis. However, our data underscore the need to study candidate mechanisms in complex in vivo conditions.…”

Section: Discussionmentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1b generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91 phox -deficient or p47 phox -deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1b levels compared with mice transplanted with wild-type bone marrow. IL-1b receptor blockade abrogated aggravated NCGN in gp91 phox -deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1b generation in gp91 phox -deficient and p47 phox -deficient monocytes compared with wild-type monocytes. This enhanced IL-1b generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1b generation were inversely related in human monocytes. Furthermore, transplantation of gp91 phox /caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91 phox bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.

show abstract

Section: Discussionmentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…The interaction between ANCA and MPO or PR-3 results in neutrophils' degranulation, subsequent endothelial damage, and the AP activation. Due to the AP activation, more C3a is generated and enhances inflammatory responses by recruiting more neutrophils [132,138,139]. However, the role of the AP in pauci-immune GN may be much more complicated.…”

Section: Pauci-immune Gnmentioning

confidence: 99%

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

2018

View full text Add to dashboard Cite

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.

show abstract

“…ANCA ağırlıklı olarak IgG yapısında olup monositlerin ve özellikle nötrofillerin sitoplazmik granüllerine karşı gelişen otoantikorlardır (19). ANCA ilişkili vaskülitler terimi; ANCA pozitifliği olan ve birbirinden farklı ancak ortak bazı bulgulara sahip olan hastalık grubunu tanımlar (20).…”

Section: Türk Nefroloji Diyaliz Ve Transplantasyon Dergisi Turkish Neunclassified

Crescentic Henoch-Schonlein Purpura Nephritis and p-ANCA Positivity in a Case with Advanced Age

Yıldız¹,

Ünlü²,

Çavdar³

et al. 2016

Turk Neph Dial Transpl

View full text Add to dashboard Cite

ÖzHenoch-Schönlein purpurası (HSP) sıklıkla çocuklarda görülen, purpurik döküntü, artrit, nefrit ve gastrointestinal semptomlar ile karakterize sistemik küçük damar vaskülitidir. Yazıda perinükleer anti-nötrofil sitoplazmik antikor (p-ANCA) pozitifliği saptanan ileri yaş kresentik HSP nefriti olgusu sunulmuştur.Olgu 78 yaşında ve erkek idi. İdrarda azalma, nefes darlığı, karın ağrısı, eklem ağrısı ve ödem yakınmaları ile hastanemize başvurdu. Fizik bakıda gluteal bölgede ve her iki alt ekstremitede purpura tarzında döküntüler vardı. Böbrek yetmezliği, proteinüri ve hematüri saptandı. Nefroloji kliniğine yatırıldı ve hemodiyaliz tedavisine başlandı. Cilt biyopsisinde damar duvarlarında granüler IgA depolanması ve böbrek biyopsisinde kresentik IgA saptandı. Kresentik HSP nefriti düşünüldü. Serum kompleman düzeyleri normal sınırlarda ölçülen olguda p-ANCA pozitifliği saptandı. Plazmaferez tedavisi ile birlikte damardan yüksek doz metilprednizolon ve siklofosfamid tedavisi uygulandı.HSP sistemik bir küçük damar vasküliti olmasına rağmen serum kompleman düzeyleri genellikle normaldir ve ANCA negatiftir. Literatürde çok nadir de olsa ANCA pozitifliği saptanan HSP olguları bildirilmiştir. HSP'de saptanan ANCA pozitifliğinin nedeni tam olarak bilinmemektedir. Kresentik HSP nefriti olgularında genellikle yüksek doz kortikosteroidlerle kombine edilen immünsüpresif ajanlar ve plazmaferez tedavisi önerilmektedir.anahTaR SÖzCÜklER: Henoch-Schönlein purpurası, Kresentik glomerülonefrit, P-ANCA aBSTRaCT Henoch-Schönlein purpura (HSP) is a vasculitis characterized by purpuric rash, arthritis, nephritis and gastrointestinal symptoms and it is generally seen in children. We report here a case of crescentic HSP nephritis with perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) positivity.Our case was 78-year-old man. He had admitted to hospital with complaints of oliguria, dyspnea, abdominal pain, arthralgia and edema. Purpuric eruptions were observed on the gluteal region and lower extremities on physical examination. He had renal failure, proteinuria and hematuria. Hemodialysis treatment was begun after hospitalisation. Granular deposits of IgA were found in vessel walls of the skin and crescentic IgA nephritis was detected in biopsy. He was considered to be suffering from crescentic HSP nephritis. Complement levels were normal, but p-ANCA was positive. High doses of methylprednisolone and cyclophosphamide were administered in addition to plasmapheresis.Although HSP is a small vessel vasculitis, serum complement levels are generally normal and ANCA is negative. Only a few cases of HSP with ANCA positivity have been reported in the literature. The reason of the ANCA positivity in patients with HSP is not exactly known.High-dose corticosteroids in combination with immunosuppressive agents and plasmapheresis are generally recommended in cases of crescentic HSPN nephritis.kEY wORdS: Henoch-Schönlein purpura, Crescentic glomerulonephritis, P-ANCA

show abstract

How anti-neutrophil cytoplasmic autoantibodies activate neutrophils

Cited by 92 publications

References 80 publications

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

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

Crescentic Henoch-Schonlein Purpura Nephritis and p-ANCA Positivity in a Case with Advanced Age

Contact Info

Product

Resources

About