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Mechanisms of vascular damage in ANCA vasculitis

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Abstract

The discovery of anti-neutrophil cytoplasmic antibodies (ANCA) and their antigenic targets, myeloperoxidase (MPO) and proteinase 3 (PR3), has led to further understanding as to the pathophysiologic processes that underlie vascular and tissue damage in ANCA vasculitis. ANCA trigger neutrophil activation leading to vascular damage in ANCA vasculitis. However, decades of study have determined that neutrophil activation alone is not sufficient to cause disease. Inflammatory stimuli are drivers of ANCA autoantigen expression and ANCA production. Certain infections or bacterial peptides may be crucial players in the initial steps of ANCA immunopathogenesis. Genetic and epigenetic alterations of gene encoding for MPO and PR3 provide additional disturbances to the immune homeostasis which provide a substrate for pathogenic ANCA formation from an adaptive immune system predisposed to autoreactivity. Promoted by inflammatory cytokines, ANCA binding leads to neutrophil activation, a process characterized by conformational changes, production and release of cytotoxic substances, and alternative complement pathway activation, thus creating an intense inflammatory milieu. This cascade of events perpetuates a vicious cycle of further inflammatory cell recruitment and activation, culminating in tissue necrosis. Our understanding of the pathogenic process in ANCA vasculitis paves the way for the development of therapies targeting crucial steps in this process. The greater appreciation of the role for complement, monocytes, and the adaptive immune system has already led to novel complement blockers and is poised to lead to further innovations which will allow for tailored antigen- or cell-specific immunotherapy targeting the autoimmune process without exposure to undue risks or toxicities.

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source of perpetual ANCA formation. Abbreviations: ANCA, anti-neutrophil cytoplasmic antibodies; MAC, membrane attack complex; MPO, myeloperoxidase; NET, neutrophil extracellular trap; PR3, proteinase 3; TF, tissue factor; TNF-α, tumor necrosis factor α

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Acknowledgements

Special thanks to Jean Brown who provided word editing and inserted the reference citations, and to Joshua Terrell who helped create the illustrative Figures 1 and 5.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

    David Massicotte-Azarniouch, Carolina A. Herrera, Ronald J. Falk & Meghan E. Free

  2. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Carolina A. Herrera & J. Charles Jennette

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  1. David Massicotte-Azarniouch
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  2. Carolina A. Herrera
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DMA and MEF conceived the outline for the manuscript. DMA, CAH, and MEF wrote the first draft. JCJ and RJF provided revisions and editing. JCJ provided the pictures. DMA, CAH, and MEF designed the illustrative figures.

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Correspondence to Meghan E. Free.

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This article is a contribution to the special issue on: Inflammation in vascular diseases - Guest Editors: Mariana Kaplan & Peter Grayson

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Massicotte-Azarniouch, D., Herrera, C.A., Jennette, J.C. et al. Mechanisms of vascular damage in ANCA vasculitis. Semin Immunopathol 44, 325–345 (2022). https://doi.org/10.1007/s00281-022-00920-0

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