Figure 1. Initiation of vasculitic lesions in small vessels by ANCA-activating cytokine-primed neutrophils in the wrong place and at the wrong time. Figure 1. Initiation of vasculitic lesions in small vessels by ANCA-activating cytokine-primed neutrophils in the wrong place and at the wrong time. Local release of inflammatory cytokines such as tumor necrosis factor (TNF), both prime neutrophils so that target antigens for ANCA are expressed on the cell surface and locally activate endothelial cells to upregulate their expression of adhesion molecules. ANCA can then bind and activate neutrophils (AcPMN) leading to (a) enhanced adhesion of activated neutrophils to activated endothelial cells (AcEC), (b) dysregulated apoptosis, secondary necrosis (nPMN), and (c) enhanced neutrophil migration across the endothelial barrier. Endothelial cells may be damaged directly by inflammatory mediators released from activated neutrophils, or they may be damaged as neutrophils undergo secondary necrosis in the vascular lumina, amplifying inflammation. After initiation of the vasculitic lesion by the interactions of neutrophils, ANCA, and endothelial cells, further mononuclear leukocytes are recruited, further enhancing vascular inflammation and injury. Lavanya Kamesh et al. JASN 2002;13:1953-1960 ©2002 by American Society of Nephrology