How do ANCAs contribute to the development of AAV?
It is not known how ANCAs contribute to the development of AAV, but several hypotheses have been proposed. Under certain conditions such as infections and other environmental triggers, release of cytokines (IL-1, tumor necrosis factor [TNF] α) can induce neutrophils and monocytes to transport PR3 or MPO to their cell surface. Patients with c-ANCA antibody can react with PR3, whereas patients with p-ANCA react with MPO, causing activation of neutrophils and monocytes. Cytokines (IL-1, TNFα) also upregulate adhesion molecules on endothelial cells, which the activated neutrophils can bind to and transmigrate into the vessel wall causing vasculitis. The circulating activated neutrophils and monocytes can degranulate and release reactive oxygen species and lysosomal enzymes, leading to endothelial injury. Other products (e.g., PR3, MPO) released from these degranulating cells may bind to the endothelial cells and serve as target antigens for circulating ANCAs, further contributing to the vasculitic response.
