title: Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.
abstract: Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener's granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ⁻/⁻ mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.
authors.affiliation: Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom. mark.little@ucl.ac.uk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Little
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ren
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Nuaimi
authors.forename: Maurilo
authors.initials: M
authors.lastname: Leite
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Savage
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006417:Hematuria / Q000209:etiology / Q000473:pathology; D006470:Hemorrhage / Q000209:etiology / Q000473:pathology; D006801:Humans; D007107:Immune System / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053146:Myeloblastin / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000235:genetics
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D015375:Receptors, Interleukin-2; D053146:Myeloblastin