title: Anti-neutrophil cytoplasmic antibodies stimulate release of neutrophil microparticles.
abstract: The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCAs) may contribute to the pathogenesis of ANCA-associated vasculitis are not well understood. In this study, both polyclonal ANCAs isolated from patients and chimeric proteinase 3-ANCA induced the release of neutrophil microparticles from primed neutrophils. These microparticles expressed a variety of markers, including the ANCA autoantigens proteinase 3 and myeloperoxidase. They bound endothelial cells via a CD18-mediated mechanism and induced an increase in endothelial intercellular adhesion molecule-1 expression, production of endothelial reactive oxygen species, and release of endothelial IL-6 and IL-8. Removal of the neutrophil microparticles by filtration or inhibition of reactive oxygen species production with antioxidants abolished microparticle-mediated endothelial activation. In addition, these microparticles promoted the generation of thrombin. In vivo, we detected more neutrophil microparticles in the plasma of children with ANCA-associated vasculitis compared with that in healthy controls or those with inactive vasculitis. Taken together, these results support a role for neutrophil microparticles in the pathogenesis of ANCA-associated vasculitis, potentially providing a target for future therapeutics.
authors: Infectious Diseases and Microbiology Unit, 30 Guilford Street, London WC1N 1EH, United Kingdom. y.hong@ich.ucl.ac.uk
authors: Ying
authors: Y
authors: Hong
authors: Despina
authors: D
authors: Eleftheriou
authors: Abdullah A K
authors: AA
authors: Hussain
authors: Fiona E
authors: FE
authors: Price-Kuehne
authors: Caroline O
authors: CO
authors: Savage
authors: David
authors: D
authors: Jayne
authors: Mark A
authors: MA
authors: Little
authors: Alan D
authors: AD
authors: Salama
authors: Nigel J
authors: NJ
authors: Klein
authors: Paul A
authors: PA
authors: Brogan
mesh_terms: D000293:Adolescent; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000276:immunology*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000502:physiology*; D001324:Autoantigens / Q000097:blood*; D018821:CD18 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D053146:Myeloblastin / Q000276:immunology; D018375:Neutrophil Activation; D009195:Peroxidase / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001324:Autoantigens; D018821:CD18 Antigens; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D013917:Thrombin; D053146:Myeloblastin