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Published online before print July 8, 2005

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(Journal of Leukocyte Biology. 2005;78:992-1000.)
© 2005 by Society for Leukocyte Biology

Anti-proteinase 3 antibodies (c-ANCA) prime CD14-dependent leukocyte activation

Katja Hattar^*, Sandra van Bürck^*, Annette Bickenbach^*, Ulrich Grandel^*, Ulrich Maus^*,, Jürgen Lohmeyer^*, Elena Csernok, Thomas Hartung, Werner Seeger^*, Friedrich Grimminger^* and Ulf Sibelius^*,1

^* Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany;
Hannover Medical School, Department of Internal Medicine, Germany;
Department of Rheumatology, Medical University of Lübeck, Germany; and
Department of Biochemical Pharmacology, University of Konstanz, Germany

¹Correspondence: Department of Internal Medicine, Justus-Liebig-University Giessen, D-35385 Giessen, FRG. E-mail: ulf.sibelius{at}innere.med.uni-giessen.de

In Wegener’s granulomatosis (WG), a pathogenetic role has been proposed for circulating anti-neutrophil-cytoplasmic antibodies (ANCA) targeting proteinase 3 (PR3). Disease activation in WG appears to be triggered by bacterial infections. In the present study, we characterized the effect of anti-PR3 antibodies on in vitro activation of isolated monocytes and neutrophils by the bacterial cell-wall components lipopolysaccharide (LPS) and lipoteichoic acid (LTA). Although sole incubation of monocytes and neutrophils with monoclonal anti-PR3 antibodies induced the release of minor quantities of the chemokine interleukin-8 (IL-8), preincubation with anti-PR3 antibodies, but not with isotype-matched control immunogloblin G (IgG), resulted in a markedly enhanced IL-8 liberation upon LPS challenge. The priming response was evident after 2 h of preincubation with anti-PR3 and peaked after 6 h. The anti-PR3-related priming was also observed for tumor necrosis factor (TNF-) and IL-6 synthesis. Comparable priming occurred when leukocytes were preincubated with ANCA-IgG derived from WG serum but not with normal IgG. The priming effect of the anti-PR3 antibody pretreatment was reproduced for LTA challenge of monocytes and neutrophils but not for leukocyte stimulation with TNF-. Flow cytometric analysis revealed an increase in monocyte and neutrophil membrane CD14 expression during the anti-PR3 priming. We conclude that cytoplasmic ANCA specifically prime CD14-dependent monocytes and neutrophils for activation. The resulting enhanced responsiveness to bacterial pathogens may contribute to the development and maintenance of inflammatory lesions during active WG.

Key Words: monocytes/macrophages • neutrophils • autoantibodies • cell surface molecules • cytokines

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