Figure 1. Immunogenesis and pathogenesis of ANCA disease.

Diagram of putative events in the pathogenesis of ANCA disease based on in vitro and in vivo experimental observations. In the upper left, the theory of autoimmunity induced by an immune response to a complementary peptide is depicted. The lower left proposes that T cell regulation is disturbed to allow persistence and progression of autoimmunity. In the upper right, the aberrant increased production of ANCA antigens by epigenetic dysregulation of gene expression is illustrated. Once ANCA antibodies are present along with neutrophils with increased antigens, the sequence of pathogenic events illustrated in the lower right can occur, i.e. cytokines or other priming factors induce neutrophils to express more ANCA antigens at the cell surface where they are available for binding to ANCA, which activates neutrophils by both Fc receptor engagement and Fab’2 binding. Factors released by neutrophils activate the alternative complement pathway, which generates factors that amplify recruitment and activation of neutrophils. Activated neutrophils release toxic factors that cause inflammatory injury to endothelial cells and vessel walls. (Reproduced with permission of J.C. Jennette)