Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies (ANCA) leads to enhanced uptake by macrophages and increased release of tumour necrosis factor-alpha (TNF-alpha)

Since proteinase 3 (PR3)-ANCA interact with PR3 on the surface of apoptotic polymorphonuclear neutrophils (PMN) and ingestion of apoptotic PMN is know n to modulate macrophage inflammatory reactions, we raised the question whe ther PR3-ANCA-opsonized apoptotic PMN influence the uptake by macrophages a nd their state of activation. We therefor analysed the effects of PR3-ANCA- opsonized apoptotic PMN on the uptake process by enzymatic assay. We furthe r investigated the production of TNF-alpha, IL-10, IL-12 and the secretion of lipid inflammatory mediators (TxB(2), leukotriene B-4 (LTB4) and prostag landin E-2 (PGE(2))) by human monocyte-derived macrophages using FACS and E LISA methods. We show that PMN-opsonization by PR3-ANCA substantially enhan ces phagocytosis by macrophages and thereby triggers the production of TNF- alpha and TxB(2). These in vitro findings indicate that PR3-ANCA opsonizati on of apoptotic PMN might be an important mechanism in the pathogenesis of Wegener's granulomatosis (WG), prompting macrophages to produce proinflamma tory mediators. These mediators, mainly TNF-alpha, might prime further PMN leading to perpetuation of the known priming-dependent mechanisms of ANCA a ction.