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  • Review Article
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Complement in ANCA-associated vasculitis: mechanisms and implications for management

Nature Reviews Nephrology volume 13, pages 359–367 (2017)Cite this article

Subjects

Key Points

  • Activation of the complement system through the alternative pathway is necessary for the development of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in animal models

  • C5a has a key role in AAV, linking inflammation and the coagulation system

  • Neutrophils, ANCA and the complement system form a positive feedback loop in the development of AAV

  • Inhibition of the complement system, particularly by targeting C5a, is a potential therapeutic approach for AAV

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The main histological feature in the kidneys of patients with AAV is pauci-immune necrotizing crescentic glomerulonephritis with little immunoglobulin and complement deposition in the glomerular capillary walls. The complement system was not, therefore, initially thought to be associated with the development of AAV. Accumulating evidence from animal models and clinical observations indicate, however, that activation of the complement system — and the alternative pathway in particular — is crucial for the development of AAV, and that the complement activation product C5a has a central role. Stimulation of neutrophils with C5a and ANCA not only results in the neutrophil respiratory burst and degranulation, but also activates the coagulation system and generates thrombin, thus bridging the inflammation and coagulation systems. In this Review, we provide an overview of the clinical, in vivo and in vitro evidence for a role of complement activation in the development of AAV and discuss how targeting the complement system could provide opportunities for therapy.

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Figure 1: Pathways of complement activation.
Figure 2: Expression of complement activation products in renal samples from patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV).
Figure 3: Proposed model for the interaction of anti-neutrophil cytoplasmic antibody (ANCA), neutrophils and complement activation in the pathogenesis of ANCA-associated vasculitis.

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Acknowledgements

The authors' work is supported by three grants of the National Natural Science Fund (No. 81425008, No. 81621092 and No. 81370829) and a grant from the National Key Research and Development Program (No. 2016YFC0906102). We are very grateful to Dr. Chen Wang for drawing the first draft of figures for this article. David Jayne is supported by the Cambridge Biomedical Research Centre.

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, 100034, P. R. China

    Min Chen & Ming-Hui Zhao

  2. Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, Cambridge, UK

    David R. W. Jayne

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All authors researched the data for the article, provided substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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PowerPoint slides

Glossary

Polyangiitis

Inflammation involving multiple blood vessels.

Vasculitides

A group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected.

Fluid phase

In the context of complement activation, fluid phase refers to activation in the circulation, rather than on the surface of cells.

Properdin

The only known positive regulator of complement activation that stabilizes the alternative pathway convertases.

Glomerular capillary tuft infarction

Occlusion of the lumen of glomerular capillaries by micro-thrombi.

Opsonize

To make bacteria or other cells more susceptible to the action of phagocytes via a mechanism involving binding of an opsonin, such as IgG or C3b

Plasma exchange

Removal, treatment and return or exchange of blood plasma or components from and to the circulation; often used to treat severe autoimmune diseases.

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Chen, M., Jayne, D. & Zhao, MH. Complement in ANCA-associated vasculitis: mechanisms and implications for management. Nat Rev Nephrol 13, 359–367 (2017). https://doi.org/10.1038/nrneph.2017.37

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