Pathogenesis and therapeutic interventions for ANCA-associated vasculitis

An Author Correction to this article was published on 17 January 2019

This article has been updated

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.

Key points

  • Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum.

  • AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and drug-induced AAV.

  • AAV can develop in patients with a genetically predisposing background who are exposed to causative environmental factors, such as infectious agents, drugs and air pollutants.

  • ANCAs have a central role in the pathogenesis of AAV because they induce excessive activation of neutrophils, which results in injury to small vessels.

  • Other immune cells (such as dendritic cells, macrophages, B cells and T cells), the complement system and humoral factors are also involved in the pathogenesis of AAV.

  • Elucidation of the aetiology and pathogenesis of AAV is needed to develop new biomarkers as well as novel targeted therapeutic agents.

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Fig. 1: NETs are found in necrotizing lesions associated with MPA but not PAN.
Fig. 2: Common pathways in the pathogenesis of AAV.
Fig. 3: A vicious cycle of NET and ANCA formation is involved in the pathogenesis of AAV.

Change history

  • 17 January 2019

    In the originally published online version of this article there were errors in the Supplementary Information. All three Supplementary Tables had incorrectly numbered references. These errors have now been corrected in the HTML and PDF versions of the manuscript.

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Acknowledgements

The authors’ research was supported by a grant from the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis.

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Nature Reviews Rheumatology thanks F. Moosig and A. Rutgers, and other anonymous reviewers, for their contribution to the peer review of this work.

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A.I. wrote the manuscript and reviewed or edited the manuscript before submission. D.N., S.M. and U.T. contributed to researching data for the article and discussions of the article content.

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Correspondence to Akihiro Ishizu.

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Nakazawa, D., Masuda, S., Tomaru, U. et al. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol 15, 91–101 (2019). https://doi.org/10.1038/s41584-018-0145-y

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