Antineutrophil cytoplasmic antibodies (ANCAs) remain central to our current understanding of the pathogenesis of ANCA-associated vasculitis (AAV), and this review considers recent developments in the context of four key questions: are there targets for ANCA beyond myeloperoxidase (MPO) and proteinase 3 (PR3); are all ANCA pathogenic; how are ANCAs generated; and how do ANCA cause disease?
Our current understanding of the pathogenesis of AAV not only reinforces the central role of neutrophils but also provides a sound rationale for B-cell and complement-directed therapies.
B-cell epitope mapping raises the possibility that only a subset of ANCA may be pathogenic. Anti-lysosomal-associated membrane protein 2 autoantibodies have recently emerged as a novel form of ANCA and can be found in anti-MPO and anti-PR3 negative disease. These also provide recent evidence for molecular mimicry in the pathogenesis of AAV, but a definitive proof in human AAV remains elusive. Neutrophil extracellular traps may represent an important mechanism by which MPO and PR3 are taken up by dendritic cells for presentation to the adaptive immune system, and the role of the alternative pathway of complement in AAV has recently been emphasized, with therapeutic implications.