Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease
- 8 July 2014
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Rheumatology
- Vol. 10 (8), 463-473
- https://doi.org/10.1038/nrrheum.2014.103
Abstract
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.This publication has 106 references indexed in Scilit:
- The role of myeloperoxidase and myeloperoxidase–antineutrophil cytoplasmic antibodies (MPO-ANCAs) in the pathogenesis of human MPO-ANCA-associated glomerulonephritisClinical and Experimental Nephrology, 2013
- The Role of the Innate Immune System in Granulomatous DisordersFrontiers in Immunology, 2013
- Animal models of antineutrophil cytoplasm antibody-associated vasculitisCurrent Opinion in Rheumatology, 2012
- Nomenclature and classification of vasculitis: lessons learned from granulomatosis with polyangiitis (Wegener's granulomatosis)Clinical and Experimental Immunology, 2011
- Patients with Wegener’s granulomatosis demonstrate a relative deficiency and functional impairment of T‐regulatory cellsImmunology, 2010
- Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritisClinical and Experimental Immunology, 2009
- Netting neutrophils in autoimmune small-vessel vasculitisNature Medicine, 2009
- ANCA patients have T cells responsive to complementary PR-3 antigenKidney International, 2008
- Molecular mimicry in pauci-immune focal necrotizing glomerulonephritisNature Medicine, 2008
- Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytesAnnals Of The Rheumatic Diseases, 2007