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Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease

Key Points

  • Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with and probably cause pauci-immune systemic necrotizing small-vessel vasculitis and glomerulonephritis

  • ANCAs specific for proteinase 3 or myeloperoxidase occur with organ-limited disease, microscopic polyangiitis, granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis

  • ANCAs seem to cause vasculitis by activating circulating primed neutrophils and causing them to attach to, penetrate and damage vessel walls by undergoing respiratory burst, degranulation, NETosis, apoptosis and necrosis

  • ANCA-induced neutrophil activation also releases factors that activate the alternative complement pathway, which establishes a destructive inflammatory amplification loop that attracts and activates more neutrophils that, in turn, further activates the complement system

  • ANCA-associated granulomatosis might result from the same pathogenic sequence of events involving extravascular primed neutrophils and interstitial-fluid ANCAs, followed by a granulomatous reaction to wall off the resulting extravascular necrosis

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.

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Figure 1: Diagram depicting the predominant types of vessels affected by major categories of systemic vasculitis.
Figure 2: Vascular and glomerular pathology of AAV.
Figure 3: Pathology of ANCA-associated necrotizing granulomatosis.
Figure 4: Diagram of the induction of an ANCA-mediated autoimmune response by an initial immune response to a peptide that is complementary to an autoantigen peptide.
Figure 5: Putative sequence of pathogenic events in ANCA-mediated vasculitis.
Figure 6: Putative sequence of pathogenic events in ANCA-mediated necrotizing granulomatosis.

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Acknowledgements

The authors are supported by a grant from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (P01-DK058335-11).

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J.C.J. researched data for the article, and both authors contributed equally to discussions of content, writing and review/editing of the manuscript before submission.

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Correspondence to J. Charles Jennette.

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J.C.J. has acted as a consultant for Amicus Therapeutics, Genentech, GlaxoSmithKline and Protalix BioTherapeutics, and has undertaken research in collaboration with ChemoCentryx. R.J.F. declares no competing interests.

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Jennette, J., Falk, R. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 10, 463–473 (2014). https://doi.org/10.1038/nrrheum.2014.103

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