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Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice

Item Type:Article
Title:Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice
Creators Name:Schreiber, A. and Eulenberg-Gustavus, C. and Bergmann, A. and Jerke, U. and Kettritz, R.
Abstract:ANCA to either PR3 or MPO are found in patients with necrotizing vasculitis and glomerulonephritis. ANCA binding to their target antigens on neutrophils and subsequent neutrophil activation are pivotal disease mechanisms that lead to vascular inflammation and necrosis. ANCA interaction with PR3 is more complex than with MPO as the neutrophil-specific CD177 receptor is involved in PR3 surface expression and PR3-ANCA-induced neutrophil activation. Modeling human disease is important to clinical research. Highly successful mouse models of MPO-ANCA vasculitis exist; however, recapitulating PR3-ANCA vasculitis has not been successful. We generated double-transgenic (DT) mice that expressed human PR3 and CD177 under a myeloid-specific huMRP8 promoter in an attempt to model PR3-ANCA vasculitis. DT mice strongly expressed the human transgenes in and on murine neutrophils and bound murine and human anti-PR3 antibodies. Nevertheless, passive transfer of these antibodies into LPS-primed DT mice or immunization of C57BL/6 mice with human PR3 followed by irradiation and transplantation of DT bone marrow failed to induce glomerulonephritis. Further analyses revealed that anti-PR3 antibodies did not activate DT neutrophils as shown by superoxide generation. Moreover, we found that mice did not properly process human pro-PR3 into mature PR3 and, consequently, the signaling complex between PR3, CD177, and CD11b, which promotes neutrophil activation by anti-PR3 antibodies, failed to form. We conclude that important species differences in PR3 and CD177 exist between men and mice that prevented successful generation of a murine anti-PR3 antibody model.
Keywords:Autoantigens, CD177, Inflammation, Animals, Mice
Source:Journal of Leukocyte Biology
Page Range:1443-1452
Date:December 2016
Official Publication:https://doi.org/10.1189/jlb.5A0116-037R
PubMed:View item in PubMed

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