Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fcγ receptor ligation

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Abstract
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 Fcγ receptors (FcγR). Because roles for phospholipase D (PLD) and phosphatidylinositol 3 kinase (PI3K) have been demonstrated in FcγR activation of neutrophils, this study investigated the hypothesis that ANCA stimulation of neutrophils involved a similar engagement of FcγR and activation of PLD and PI3K. Pretreatment of tumor necrosis factor (TNF) α-primed neutrophils with antibodies against FcγRII and FcγRIII inhibited MPO-ANCA and PR3-ANCA induced superoxide generation, confirming that FcγR ligation is involved in ANCA-mediated neutrophil activation. However, although stimulation of TNF-α–primed neutrophils by conventional FcγR ligation, either using antibody-mediated cross-linking of FcγR or aggregated IgG, induced PLD activation, ANCA stimulation did not. Moreover, although ANCA-induced neutrophil activation results in significant PI3K activation—as assessed by phosphatidylinositol 3,4,5-triphosphate generation—conventional FcγR 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/p110γ PI3K isoform. In addition, the kinetics of activation of protein kinase B differs between conventional FcγR ligation and ANCA stimulation of neutrophils. These results demonstrate that though ligation of FcγRIIa and FcγRIIIb may be necessary, it is likely that ANCAs require other membrane cofactors for neutrophil activation.

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