Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: Role of exogenous arachidonic acid and leukotriene B4 generation

Friedrich Grimminger*, Katja Hattar, Charis Papavassilis, Bettina Temmesfeld, Elena Csernok, Wolfgang Ludwig Gross, Werner Seeger, Ulf Sibelius

*Korrespondierende/r Autor/-in für diese Arbeit
81 Zitate (Scopus)


Among the anti-neutrophil cytoplasmic antibodies (ANCA), those targeting proteinase 3 (PR3) have a high specificity for Wegener's granulomatosis (WG). It is known that a preceding priming of neutrophils with cytokines is a prerequisite for membrane surface expression of PR3, which is then accessible to autoantibody binding. Employing a monoclonal antibody directed against human PR3 and ANCA-positive serum from WG patients with specificity for PR3, we now investigated the role of free arachidonic acid (AA) in autoantibody- related human neutrophil activation. Priming of neutrophils with tumor necrosis factor (TNF-α) for 15 min or exposure to anti-PR3 antibodies of incubation with free AA (10 μM) as sole events did not provoke superoxide generation, elastase secretion or generation of 5-lipoxygenase products of AA. Similarly, the combination of TNF-α-priming and AA incubation was ineffective. When TNF-α-primed neutrophils were stimulated by anti-PR3 antibodies, superoxide and elastase secretion was provoked in the absences of lipid mediator generation. However, when free AA was additionally provided, a strong activation of the 5-lipoxygenase pathway was demasked, with the appearance of excessive quantities of leukotriene (LT)B4, LTA4 and 5- hydroxyeicosatetraenoic acid. Moreover, superoxide and elastase secretion were markedly amplified, and studies with 5-lipoxygenase inhibitors and a LTB4-antagonist demonstrated this was due to an LTB4-related autocrine loop of cell activation. In contrast, the increased synthesis of platelet- activating factor in response to TNF-α-priming and anti-PR3 stimulation did not contribute to the amplification loop of neutrophil activation under the given conditions. We conclude that anti-PR3 antibodies are potent inductors of the 5-lipoxygenase pathway in primed human neutrophils, and extracellular free AA, as provided at an inflammatory focus, synergizes with the autoantibodies to evoke fill-blown lipid mediator generation, granule secretion and respiratory burst. Such events may be enrolled in the pathogenesis of focal necrotizing vascular injury in Wegener's granulomatosis.

ZeitschriftJournal of Experimental Medicine
Seiten (von - bis)1567-1572
PublikationsstatusVeröffentlicht - 01.10.1996

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)


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