TY - JOUR
T1 - Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: Role of exogenous arachidonic acid and leukotriene B4 generation
AU - Grimminger, Friedrich
AU - Hattar, Katja
AU - Papavassilis, Charis
AU - Temmesfeld, Bettina
AU - Csernok, Elena
AU - Gross, Wolfgang Ludwig
AU - Seeger, Werner
AU - Sibelius, Ulf
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1996/10/1
Y1 - 1996/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0029956513&partnerID=8YFLogxK
U2 - 10.1084/jem.184.4.1567
DO - 10.1084/jem.184.4.1567
M3 - Journal articles
C2 - 8879231
AN - SCOPUS:0029956513
SN - 0022-1007
VL - 184
SP - 1567
EP - 1572
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -