Mechanisms of vascular damage in ANCA vasculitis

• Published in: Seminars in immunopathology 2022-05, Vol.44 (3), p.325-345
• Main Authors: Massicotte-Azarniouch, David, Herrera, Carolina A., Jennette, J. Charles, Falk, Ronald J., Free, Meghan E.
• Format: Article
• Language: English
• Subjects: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - etiology; Antibodies, Antineutrophil Cytoplasmic; Antineutrophil cytoplasmic antibodies; Autoantigens; Biomedical and Life Sciences; Biomedicine; Cell activation; Complement activation; Cytokines; Cytotoxicity; Epigenetics; Homeostasis; Humans; Immune system; Immunology; Immunopathogenesis; Immunotherapy; Internal Medicine; Leukocytes (neutrophilic); Monocytes; Monocytes - metabolism; Myeloblastin - genetics; Neutrophils; Pathology; Peroxidase; Proteinase 3; Review; Vasculitis; Vasculitis - metabolism
• ISSN: 1863-2297; 1863-2300
• DOI: 10.1007/s00281-022-00920-0

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.