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J. Exp. Med.,
Volume 187, Number 4, February 16, 1998 497-503
By
From the * Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany;
the 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 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
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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