title: Anti-proteinase 3 antibodies (c-ANCA) prime CD14-dependent leukocyte activation.
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 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 alpha (TNF-alpha) 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-alpha. 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.
authors: Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
authors: Katja
authors: K
authors: Hattar
authors: Sandra
authors: S
authors: van Bürck
authors: Annette
authors: A
authors: Bickenbach
authors: Ulrich
authors: U
authors: Grandel
authors: Ulrich
authors: U
authors: Maus
authors: Jürgen
authors: J
authors: Lohmeyer
authors: Elena
authors: E
authors: Csernok
authors: Thomas
authors: T
authors: Hartung
authors: Werner
authors: W
authors: Seeger
authors: Friedrich
authors: F
authors: Grimminger
authors: Ulf
authors: U
authors: Sibelius
mesh_terms: D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007074:Immunoglobulin G / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D013682:Teichoic Acids / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D016207:Cytokines; D007074:Immunoglobulin G; D015850:Interleukin-6; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid