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, Ulf Sibelius

Research output: Contribution to journalArticlepeer-review

Abstract

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 imniunogloblin 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 α (TNF-α) and IL-6 synthesis. Comparable priming occurred when leukocytes were prehicubated 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-α. 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.

Original languageEnglish (US)
Pages (from-to)992-1000
Number of pages9
JournalJournal of Leukocyte Biology
Volume78
Issue number4
DOIs
StatePublished - Oct 2005
Externally publishedYes

Keywords

  • Autoantibodies
  • Cell surface molecules
  • Cytokines
  • Monocytes/macrophages
  • Neutrophils

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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