Anti–neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specifity for Wegener's granulomatosis (WG), and their role in activating leukocytes is well appreciated. In this study, we investigated the influence of PR3-ANCA and murine monoclonal antibodies on human umbilical vascular endothelial cells (HUVECs). Priming of HUVECs with tumor necrosis factor α induced endothelial upregulation of PR3 message and surface expression of this antigen, as measured by Cyto-ELISA, with a maximum occurrence after 2 h. Primed cells responded to low concentrations of both antibodies (25 ng–2.5 μg/ml), but not to control immunoglobulins, with pronounced, dose-dependent phosphoinositide hydrolysis, as assessed by accumulation of inositol phosphates. The signaling response peaked after 20 min, in parallel with the appearance of marked prostacyclin and platelet-activating factor synthesis. The F(ab)2 fragment of ANCA was equally potent as ANCA itself. Disrupture of the endothelial F-actin content by botulinum C2 toxin to avoid antigen–antibody internalization did not affect the response. In addition to the metabolic events, anti-PR3 challenge, in the absence of plasma components, provoked delayed, dose-dependent increase in transendothelial protein leakage. We conclude that anti-PR3 antibodies are potent inductors of the preformed phosphoinositide hydrolysis–related signal tranduction pathway in human endothelial cells. Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3–induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG.
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16 February 1998
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February 16 1998
Wegener's Granulomatosis: Anti–proteinase 3 Antibodies Are Potent Inductors of Human Endothelial Cell Signaling and Leakage Response
Ulf Sibelius,
Ulf Sibelius
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Katja Hattar,
Katja Hattar
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Angelika Schenkel,
Angelika Schenkel
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Thomas Noll,
Thomas Noll
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Elena Csernok,
Elena Csernok
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Wolfgang Ludwig Gross,
Wolfgang Ludwig Gross
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Werner-Johannes Mayet,
Werner-Johannes Mayet
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Hans-Michael Piper,
Hans-Michael Piper
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Werner Seeger,
Werner Seeger
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Friedrich Grimminger
Friedrich Grimminger
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
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Ulf Sibelius
,
Katja Hattar
,
Angelika Schenkel
,
Thomas Noll
,
Elena Csernok
,
Wolfgang Ludwig Gross
,
Werner-Johannes Mayet
,
Hans-Michael Piper
,
Werner Seeger
,
Friedrich Grimminger
From the *Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany; the ‡Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany; the §Department of Rheumatology of the Medical University of Lübeck, 23538 Lübeck, Germany; and the ‖First Medical Department, University of Mainz, 55131 Mainz, Germany
Address correspondence to Dr. F. Grimminger, Department of Internal Medicine, Justus-Liebig-University Giessen, D-35392 Giessen, FRG. Phone: 49-641-99-42500; Fax: 49-641-99-42509; E-mail: friedrich. [email protected]
1
Abbreviations used in this paper: ANCA, anti–neutrophil cytoplasmic antibodies; c-ANCA, cytoplasmic ANCA; HUVEC, human umbilical cord endothelial cell; IP, inositol phosphate; IPx, IP1, IP2, and IP3; MoAb-PR3, mAb to proteinase 3; PAF, platelet-activating factor; PR3, proteinase 3; WG, Wegener's granulomatosis.
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 547).
Received:
July 03 1997
Revision Received:
December 01 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (4): 497–503.
Article history
Received:
July 03 1997
Revision Received:
December 01 1997
Citation
Ulf Sibelius, Katja Hattar, Angelika Schenkel, Thomas Noll, Elena Csernok, Wolfgang Ludwig Gross, Werner-Johannes Mayet, Hans-Michael Piper, Werner Seeger, Friedrich Grimminger; Wegener's Granulomatosis: Anti–proteinase 3 Antibodies Are Potent Inductors of Human Endothelial Cell Signaling and Leakage Response . J Exp Med 16 February 1998; 187 (4): 497–503. doi: https://doi.org/10.1084/jem.187.4.497
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