title: Vascular damage in Wegener's granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies.
abstract: To define mechanisms of vascular injury in Wegener's granulomatosis and microscopic polyarteritis, anti-endothelial cell antibodies (AECA) were sought in serum from 168 patients, all of whom had anti-neutrophil cytoplasm antibodies (ANCA) detectable by indirect immunofluorescence. Using an ELISA with human umbilical vein endothelial cells (HUVEC), IgG AECA were demonstrated in 59% and IgM AECA in 68% of patients. Pretreatment of HUVEC with tumour necrosis factor (TNF), IL-1 or interferon-gamma (IFN-gamma) led to increased binding. Adsorption of AECA/ANCA-containing serum with HUVEC or neutrophils demonstrated that AECA and ANCA recognized different targets. von Willebrand factor (vWf) antigen levels in the patient samples were markedly elevated, with a mean of 3.10 +/- 1.89 U/ml (control population mean 1.04 +/- 0.36 U/ml), suggesting widespread endothelial cell damage. Studies using an 111In-labelled HUVEC release assay with 29 AECA-containing sera did not demonstrate complement-mediated cytotoxicity, even following activation of HUVEC with TNF. Four out of 16 AECA-containing sera tested showed antibody-dependent cellular cytotoxicity with unfractionated peripheral blood mononuclear cells. These data suggest that patients with Wegener's granulomatosis or microscopic polyarteritis can develop AECA to constitutively expressed but cytokine modulated determinants on HUVEC. These antibodies do not appear to support complement-mediated cytotoxicity, but a proportion can support antibody-dependent cellular cytotoxicity, suggesting that they may contribute to vascular injury.
authors.affiliation: Section of Vascular Biology, MRC Clinical Research Centre, Harrow, UK.
authors.forename: C O
authors.initials: CO
authors.lastname: Savage
authors.forename: B E
authors.initials: BE
authors.lastname: Pottinger
authors.forename: G
authors.initials: G
authors.lastname: Gaskin
authors.forename: C M
authors.initials: CM
authors.lastname: Lockwood
authors.forename: C D
authors.initials: CD
authors.lastname: Pusey
authors.forename: J D
authors.initials: JD
authors.lastname: Pearson
mesh_terms: D001160:Arterioles / Q000276:immunology / Q000473:pathology; D001167:Arteritis / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000032:analysis*; D016207:Cytokines / Q000627:therapeutic use; D003593:Cytoplasm / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D014890:Granulomatosis with Polyangiitis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D009504:Neutrophils / Q000276:immunology*; D014471:Umbilical Veins / Q000187:drug effects / Q000276:immunology; D014657:Vasculitis / Q000276:immunology; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D014841:von Willebrand Factor