Pathogenesis and therapeutic interventions for ANCA-associated vasculitis

• Published in: Nature reviews. Rheumatology 2019-02, Vol.15 (2), p.91-101
• Main Authors: Nakazawa, Daigo, Masuda, Sakiko, Tomaru, Utano, Ishizu, Akihiro
• Format: Article
• Language: English
• Subjects: 692/4023/1670/595; 692/420; 692/420/2780; 692/699/249/1313; 692/700/565; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - etiology; Antibodies, Antineutrophil Cytoplasmic - physiology; Antineutrophil cytoplasmic antibodies; Autoimmune diseases; B cells; Care and treatment; Cell activation; Cytokines; Dendritic cells; Development and progression; Environmental factors; Granulomatosis; Health aspects; Humans; Immunosuppressive agents; Inflammation; Innate immunity; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lymphocytes B; Lymphocytes T; Lytic enzymes; Macrophages; Medicine; Medicine & Public Health; Methods; Molecular Targeted Therapy; Neutrophils; Neutrophils - physiology; Pathogenesis; Pollutants; Reactive oxygen species; Review Article; Rheumatology; Therapeutic applications; Vasculitis
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/s41584-018-0145-y

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. Nakazawa and colleagues describe advances in our understanding of anti-neutrophil cytoplasmic antibody-associated vasculitis. These insights have already generated promising new treatments that target B cells, T cells and cytokines; potential novel approaches targeting additional cells or molecules are also discussed. 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 hum