Antibodies to proteinase 3 increase adhesion of neutrophils to human endothelial cells

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Abstract
The detection of anti-neutrophil cytoplasmic antibodies (ANCA), especially those with specificity for proteinase 3, is important in the diagnosis and in monitoring disease activity of Wegener's granulomatosis and related vasculitides. An ubiquitous feature of all ANCA-associated acute vascular injury is lytic necrosis. Adhesion of neutrophils to endothelium is a fundamental early step of the inflammatory response. Recently we were able to show that ANCA recognize their target antigen (proteinase 3) translocated into the membrane of human endothelial cells. The aim of this study was to investigate the effect of ANCA on the adhesion of neutrophils to human endothelial cells. Incubation of endothelial cells with affinity-purified antibodies to proteinase 3 (IgG- and F(ab')2-fractions) led to a marked increase of neutrophil adhesion, with a peak after 4 h and a rapid decrease after 8 h. This effect could be inhibited by preincubation of the endothelial cells with an antibody to endothelial leucocyte adhesion molecule-1 (ELAM-1). Incubation with antibodies to proteinase 3 also led to an incrcase of endothelial ELAM-1 expression as measured in a cyto-ELISA and by flow cytometry. Our data demonstrate a direct effect of ANCA on neutrophil endothelial interactions. The enhanced adhesion of neutrophils occurs time-dependently via induction of ELAM-1 expression on the surface of endothelial cells. Our data give a hint of an ANCA-mediated mechanism of endothelial injury via induction of neutrophil adhesion to vascular endothelium in Wegener's granulomatosis and other ANCA-related vasculitides.