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Review
. 2020 Oct 3;21(19):7319.
doi: 10.3390/ijms21197319.

Immunopathogenesis of ANCA-Associated Vasculitis

Andreas Kronbichler  1 , Keum Hwa Lee  2 , Sara Denicolò  1 , Daeun Choi  3 , Hyojeong Lee  3 , Donghyun Ahn  3 , Kang Hyun Kim  3 , Ji Han Lee  3 , HyungTae Kim  3 , Minha Hwang  3 , Sun Wook Jung  3 , Changjun Lee  3 , Hojune Lee  3 , Haejune Sung  3 , Dongkyu Lee  3 , Jaehyuk Hwang  3 , Sohee Kim  3 , Injae Hwang  3 , Do Young Kim  3 , Hyung Jun Kim  3 , Geonjae Cho  3 , Yunryoung Cho  3 , Dongil Kim  3 , Minje Choi  3 , Junhye Park  3 , Junseong Park  3 , Kalthoum Tizaoui  4 , Han Li  5 , Lee Smith  6 , Ai Koyanagi  7   8 , Louis Jacob  7   9 , Philipp Gauckler  1 , Jae Il Shin  2
Affiliations
Review

Immunopathogenesis of ANCA-Associated Vasculitis

Andreas Kronbichler et al. Int J Mol Sci. .

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Keywords: ANCA; biomarker; pathogenesis; phenotype; treatment.

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Conflict of interest statement

Andreas Kronbichler has received speaking or consulting fees from Vifor Pharma, Terumo BCT, Alexion and Novartis, and travel support from Vifor Pharma. Philipp Gauckler received travel support from Vifor Pharma. All other authors confirm to have no actual or potential conflict of interests.

Figures

Figure 1
Figure 1
Pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. An inflammatory trigger leads to increased membranous expression of myeloperoxidase (MPO) and proteinase 3 (PR3) on neutrophils. Binding of ANCAs to PR3 and MPO triggers neutrophil activation, degranulation, neutrophil extracellular trap (NET)osis, which further releases MPO and PR3 to prime ANCAs. Degranulation and NETosis contribute to endothelial injury and complement activation.
Figure 2
Figure 2
Phenotypes of ANCA serotypes. PR3-ANCA (purple) affects the ear nose and throat (ENT), the upper and lower respiratory tract and the kidneys in around 50–60% of cases, while MPO-ANCA (green) primarily affects the lungs and kidneys. Tumor necrosis factor (TNF)-α, C5a, interleukin (IL)-6, IL-8, and B cell activating factor (BAFF) are elevated in both PR3- and MPO-ANCA. IL-10 is elevated only in PR3-ANCA and is decreased in MPO-ANCA.
Figure 3
Figure 3
Therapeutic armamentarium of ANCA-associated vasculitis based on disease pathogenesis. TNF-α, IL-6, and alternative complement activation contribute to neutrophil priming, activation, and endothelial injury and are targeted by adalimumab, tocilizumab, and avacopan, respectively. BAFF stimulates B cell activation and is targeted by belimumab. B cells are targeted by rituximab.
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