Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.

Hdl Handle:
http://hdl.handle.net/10147/237978
Title:
Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.
Authors:
Little, Mark A; Al-Ani, Bahjat; Ren, Shuyu; Al-Nuaimi, Hamad; Leite, Maurilo; Alpers, Charles E; Savage, Caroline O; Duffield, Jeremy S
Affiliation:
Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom. mark.little@ucl.ac.uk
Citation:
Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. 2012, 7 (1):e28626 PLoS ONE
Journal:
PloS one
Issue Date:
2012
URI:
http://hdl.handle.net/10147/237978
DOI:
10.1371/journal.pone.0028626
PubMed ID:
22247758
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed?term=Anti-proteinase%203%20anti-neutrophil%20cytoplasm%20autoantibodies%20recapitulate%20systemic%20vasculitis%20in%20mice%20with%20a%20humanized%20immune%20system
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.
Item Type:
Article
Language:
en
MeSH:
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
ISSN:
1932-6203

Full metadata record

DC FieldValue Language
dc.contributor.authorLittle, Mark Aen_GB
dc.contributor.authorAl-Ani, Bahjaten_GB
dc.contributor.authorRen, Shuyuen_GB
dc.contributor.authorAl-Nuaimi, Hamaden_GB
dc.contributor.authorLeite, Mauriloen_GB
dc.contributor.authorAlpers, Charles Een_GB
dc.contributor.authorSavage, Caroline Oen_GB
dc.contributor.authorDuffield, Jeremy Sen_GB
dc.date.accessioned2012-08-09T13:45:45Z-
dc.date.available2012-08-09T13:45:45Z-
dc.date.issued2012-
dc.identifier.citationAnti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. 2012, 7 (1):e28626 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid22247758-
dc.identifier.doi10.1371/journal.pone.0028626-
dc.identifier.urihttp://hdl.handle.net/10147/237978-
dc.description.abstractEvidence 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.en_GB
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed?term=Anti-proteinase%203%20anti-neutrophil%20cytoplasm%20autoantibodies%20recapitulate%20systemic%20vasculitis%20in%20mice%20with%20a%20humanized%20immune%20systemen_GB
dc.rightsArchived with thanks to PloS oneen_GB
dc.subject.meshAnimals-
dc.subject.meshAnti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis-
dc.subject.meshAntibodies, Antineutrophil Cytoplasmic-
dc.subject.meshAutoantibodies-
dc.subject.meshFemale-
dc.subject.meshFlow Cytometry-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHematuria-
dc.subject.meshHemorrhage-
dc.subject.meshHumans-
dc.subject.meshImmune System-
dc.subject.meshImmunoenzyme Techniques-
dc.subject.meshLeukocytes-
dc.subject.meshMice-
dc.subject.meshMice, Inbred NOD-
dc.subject.meshMice, SCID-
dc.subject.meshMyeloblastin-
dc.subject.meshReceptors, Interleukin-2-
dc.titleAnti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.en_GB
dc.typeArticleen
dc.contributor.departmentCentre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom. mark.little@ucl.ac.uken_GB
dc.identifier.journalPloS oneen_GB
dc.description.provinceLeinsteren
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