Figure 2.

The role of NETs in AAV and the complex relation between ANCAs and NETs. (A) Pathogenic ANCAs (red) reacting with PR3 and MPO on the surface of neutrophils cause ROS production and the release of NETs through NETosis (34, 78, 79). (B) NETs contain various proinflammatory mediators, such as histones, HMGB1, PR3, MPO, and NE (17, 20, 21), and contribute to vessel inflammation by damaging endothelial cells (57–59) and by activating the complement system (60). (C) NETs do also promote thrombosis through the expression of histones (62) and tissue factor (63, 64). (D) NETs can also act as a link between the innate and adaptive immune system through the generation of ANCAs (41, 80). (E) ANCAs seem to belong to repertoire of “natural” antibodies (81), indicating that not all ANCAs are pathogenic, and it has been proposed that ANCAs can aid in clearance of circulating NET remnants (43). (F) However, under unfavorable circumstances, pathogenic ANCAs (red) are produced, creating a vicious circle that promotes inflammation. B, B cell; Th, T helper cell; DC, dendritic cell. Modified from Ref. (43) with permission from Oxford University Press.