Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.
AuthorsLittle, Mark A
Alpers, Charles E
Savage, Caroline O
Duffield, Jeremy S
AffiliationCentre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom. email@example.com
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Antibodies, Antineutrophil Cytoplasmic
Hematopoietic Stem Cells
Mice, Inbred NOD
MetadataShow full item record
CitationAnti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. 2012, 7 (1):e28626 PLoS ONE
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.
- Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody-associated systemic vasculitis: anti-proteinase 3-mediated neutrophil activation is independent of the role of CD177-expressing neutrophils.
- Authors: Hu N, Westra J, Huitema MG, Bijl M, Brouwer E, Stegeman CA, Heeringa P, Limburg PC, Kallenberg CG
- Issue date: 2009 May
- Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice.
- Authors: Schreiber A, Eulenberg-Gustavus C, Bergmann A, Jerke U, Kettritz R
- Issue date: 2016 Dec
- Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis.
- Authors: Primo VC, Marusic S, Franklin CC, Goldmann WH, Achaval CG, Smith RN, Arnaout MA, Nikolic B
- Issue date: 2010 Mar
- Discrimination and variable impact of ANCA binding to different surface epitopes on proteinase 3, the Wegener's autoantigen.
- Authors: Silva F, Hummel AM, Jenne DE, Specks U
- Issue date: 2010 Dec
- Expression profile of proinflammatory genes in neutrophil-enriched granulocytes stimulated with native anti-PR3 autoantibodies.
- Authors: Surmiak M, Kaczor M, Sanak M
- Issue date: 2012 Jun