ANCA-associated vasculitis — clinical utility of using ANCA specificity to classify patients

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Netting neutrophils in autoimmune small-vessel vasculitis.

Kai Kessenbrock, Markus Krumbholz, Ulf Schönermarck … (2009)

Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.

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Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

R J Falk, R Terrell, L Charles … (1990)

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are in the circulation of most patients with pauci-immune necrotizing vasculitis and pauci-immune crescentic glomerulonephritis. The current study demonstrates an effect of these autoantibodies on neutrophil function in vitro. ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. ANCA sera and purified immunoglobulins significantly increase the release of reactive oxygen species when compared with controls. ANCA, in a dose-dependent manner, induce the release of primary granule contents. These effects are markedly enhanced by priming neutrophils with tumor necrosis factor. Flow cytometry studies demonstrate the presence of myeloperoxidase on the surface of neutrophils after cytokine priming, indicating that primed neutrophils have ANCA antigens at their surfaces to interact with ANCA. These observations suggest an in vivo pathogenetic role for ANCA. We propose that, in patients with necrotizing vasculitis, ANCA-induced release of toxic oxygen radicals and noxious granule enzymes from cytokine-primed neutrophils could be mediating vascular inflammation.

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Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease.

Amanda Falk, Charles Jennette (2014)

Antineutrophil cytoplasmic autoantibodies (ANCAs) are the probable cause of a distinct form of vasculitis that can be accompanied by necrotizing granulomatosis. Clinical and experimental evidence supports a pathogenesis that is driven by ANCA-induced activation of neutrophils and monocytes, producing destructive necrotizing vascular and extravascular inflammation. Pathogenic ANCAs can originate from precursor natural autoantibodies. Pathogenic transformation might be initiated by commensal or pathogenic microbes, legal or illegal drugs, exogenous or endogenous autoantigen complementary peptides, or dysregulated autoantigen expression. The ANCA autoimmune response is facilitated by insufficient T-cell and B-cell regulation. A putative pathogenic mechanism for vascular inflammation begins with ANCA-induced activation of primed neutrophils and monocytes leading to activation of the alternative complement pathway, which sets in motion an inflammatory amplification loop in the vessel wall that attracts and activates neutrophils with resultant respiratory burst, degranulation, extrusion of neutrophil extracellular traps, apoptosis and necrosis. The pathogenesis of extravascular granulomatosis is less clear, but a feasible scenario proposes that a prodromal infectious or allergic condition positions primed neutrophils in extravascular tissue in which they can be activated by ANCAs in interstitial fluid to produce extravascular necrotizing injury that would initiate an innate granulomatous inflammatory response to wall off the necrotic debris.

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Title: Nature Reviews Rheumatology

Abbreviated Title: Nat Rev Rheumatol

Publisher: Springer Nature

ISSN (Print): 1759-4790

ISSN (Electronic): 1759-4804

Publication date Created: July 28 2016

Publication date (Print): July 28 2016

Volume: 12

Issue: 10

Pages: 570-579

Article

DOI: 10.1038/nrrheum.2016.123

PubMed ID: 27464484

SO-VID: 34a0c427-b28a-4566-ac54-49f0e70c318d

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ANCA-associated vasculitis — clinical utility of using ANCA specificity to classify patients

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Most cited references 111

Netting neutrophils in autoimmune small-vessel vasculitis.

Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease.

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