Subthreshold concentrations of anti-proteinase 3 antibodies (c-ANCA) specifically prime human neutrophils for fMLP-induced leukotriene synthesis and chemotaxis

Anti-neutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 (PR3) possess a high sensitivity anti specificity for Wegener's granulomatosis. D ue to their capacity of directly activating neutrophils, a pathogenetic rol e for these autoantibodies has been proposed We investigated the impact of subthreshold concentrations of monoclonal anti-PR3 antibodies (anti-PR3; 0. 1 mug/mL) on neutrophil activation elicited by a secondary agent. Preincuba tion with anti-PR3 resulted ill a massive amplification of N-formyl-methion yl-leucyl-phenyl-alanine (fMLP)-induced leukotriene (LT) generation, with a marked increase in the? liberation of LTB4, LTA(4), and 5-hydroxyeicosatet raenoic acid (5-HETE), This priming commenced within 2.5 min, with a maximu m after 5-7.5 min. Moreover, anti-PR3 I,rt treatment markedly enhanced PMN movement toward fMLP, The priming effect of anti-PR3 toward fMLP challenge was reproduced by c-ANCA, but not by F(ab)(2) fragments of the antibodies a nd isotype-matched control IgG, Generation of superoxide anion and release of elastase were suppressed in anti-PR3-pretreated neutrophils undergoing f MLP challenge, In contrast, neutrophil activation by platelet-activating fa ctor (PAF) or the calcium ionophore A23187 remained unaffected, We conclude that subthreshold concentrations of anti-PR3 antibodies selectively modify neutrophil responses to fMLP, with enhancement of leukotriene generation a nd chemotaxis, but suppression of respiratory burst and degranulation, Such priming might contribute to localized neutrophil accumulation together wit h blunted host defense ill Wegener's granulomatosis.