Little, MA; Al-Ani, B; Ren, S; Al-Nuaimi, H; Leite, M; Alpers, CE; ... Duffield, JS; + view all Little, MA; Al-Ani, B; Ren, S; Al-Nuaimi, H; Leite, M; Alpers, CE; Savage, CO; Duffield, JS; - view fewer (2012) Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLOS One , 7 (1) , Article e28626. 10.1371/journal.pone.0028626.
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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.
|Title:||Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||© 2012 Little et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. All studies were funded by NIH funds or MRC (UK). JSD's laboratory is supported by the Division of Nephrology and Center for Lung Biology, University of Washington, NIH grants DK73299, DK84077, DK87389 and a GRIP award from Genzyme. ML is supported by Higher Education Funding Council of England and BA is supported by Medical Research Council grant number G0801025. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.|
|Keywords:||Animals, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Antibodies, Antineutrophil Cytoplasmic, Autoantibodies, Female, Flow Cytometry, Hematopoietic Stem Cells, Hematuria, Hemorrhage, Humans, Immune System, Immunoenzyme Techniques, Leukocytes, Mice, Mice, Inbred NOD, Mice, SCID, Myeloblastin, Receptors, Interleukin-2|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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