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Related Collections Hemostasis, Thrombosis, and Vascular Biology Phagocytes Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2001, Vol. 98, No. 5, pp. 1448-1455 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fc receptor ligation Anne Ben-Smith, Stephen K. Dove, Ashley Martin, Michael J. O. Wakelam, and Caroline O. S. Savage From the Renal Immunobiology, MRC Centre for Immune Regulation, the Department of Biochemistry, and the Institute for Cancer Studies, The Medical School, University of Birmingham, United Kingdom. In systemic vasculitis, interactions between antineutrophil cytoplasm autoantibodies (ANCAs) and neutrophils initiate endothelial and vascular injury. ANCAs directed against either myeloperoxidase (MPO) or proteinase 3 (PR3) can activate cytokine-primed neutrophils by binding cell surface-expressed MPO or PR3, with the concurrent engagement of Fc receptors (FcR). Because roles for phospholipase D (PLD) and phosphatidylinositol 3 kinase (PI3K) have been demonstrated in FcR activation of neutrophils, this study investigated the hypothesis that ANCA stimulation of neutrophils involved a similar engagement of FcR and activation of PLD and PI3K. Pretreatment of tumor necrosis factor (TNF) -primed neutrophils with antibodies against FcRII and FcRIII inhibited MPO-ANCA and PR3-ANCA induced superoxide generation, confirming that FcR ligation is involved in ANCA-mediated neutrophil activation. However, although stimulation of TNF--primed neutrophils by conventional FcR ligation, either using antibody-mediated cross-linking of FcR or aggregated IgG, induced PLD activation, ANCA stimulation did not. Moreover, although ANCA-induced neutrophil activation results in significant PI3K activationas assessed by phosphatidylinositol 3,4,5-triphosphate generationconventional FcR ligation, but not ANCA, activates the p85/p110 PI3K subtype. Inhibition of ANCA-induced superoxide generation with pertussis toxin suggests that ANCAs activate the p101/p110 PI3K isoform. In addition, the kinetics of activation of protein kinase B differs between conventional FcR ligation and ANCA stimulation of neutrophils. These results demonstrate that though ligation of FcRIIa and FcRIIIb may be necessary, it is likely that ANCAs require other membrane cofactors for neutrophil activation. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. M. Uriarte, K. R. McLeish, and R. A. Ward Anti-proteinase 3 antibodies both stimulate and prime human neutrophils Nephrol. Dial. 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