Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener's granulomatosis.
Autoantibodies directed against cytoplasmic antigens of neutrophils (ANCA), especially proteinase 3 (PR-3), have proved to be a useful clinical tool confirming the diagnosis or monitoring disease activity of Wegener's granulomatosis (WG). Although several concepts concerning the pathophysiologic potentials of ANCA have been discussed, only sparse data about ANCA-endothelium interactions have been available. In this study, we have investigated the expression of PR-3 in cytokine-treated human endothelial cells using purified anti-PR-3 antibodies of patients with WG, murine and human monoclonal anti-PR-3 antibodies as probes. We were able to show that tumor necrosis factor-alpha, interleukin-1 alpha/beta, and interferon-gamma led to an increased PR-3 expression in the cytoplasm of endothelial cells by performing polymerase chain reaction analysis, Western blot, cyto-enzyme-linked immunosorbent assays, and confocal laser scanning microscopy. Moreover, PR-3 was also translocated into the cell membrane, becoming accessible to ANCA. Our data suggest a possible direct pathogenic effect of anti-PR-3 antibodies in WG and other vasculitides. Anti-PR-3 antibodies represent an important missing link in ANCA-endothelial interactions.
Mayet
W J
WJ
I. Medical Department of Medicine, University of Mainz, Germany.
Csernok
E
E
Szymkowiak
C
C
Gross
W L
WL
Meyer zum Büschenfelde
K H
KH
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000032:analysis*; D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000276:immunology*; D014890:Granulomatosis with Polyangiitis / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D053146:Myeloblastin; D012697:Serine Endopeptidases / Q000032:analysis*
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D012697:Serine Endopeptidases; D053146:Myeloblastin