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Netting neutrophils in autoimmune small-vessel vasculitis

Nature Medicine volume 15, pages 623–625 (2009)Cite this article

Abstract

Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.

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Figure 1: ANCA-induced formation of NETs containing autoantigens PR3 and MPO.
Figure 2: In vivo evidence for NET formation in individuals with SVV.

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Acknowledgements

We would like to thank W. Samtleben for providing serum samples, R. Bittner for technical assistance and E. Csernok and A. Kniepert for help with serum samples. Moreover, we are grateful to M. Sixt and E. Meinl for helpful suggestions and H. Wekerle for his constant interest and support of this work. We also thank M. Monestier (Temple University) for providing us with histone-specific monoclonal antibody and G. Koch (University of Freiburg) for the kind gift of the antibody specific for MxA. This work was funded by the Deutsche Forschungsgemeinschaft (SFB 571). It was further supported by the US National Institutes of Health (AI053194) and by fellowships from the Susan G. Komen for the Cure Foundation and the Alexander von Humboldt Foundation.

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Authors and Affiliations

  1. Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany

    Kai Kessenbrock, Markus Krumbholz & Dieter E Jenne

  2. Department of Anatomy, University of California, San Francisco, California, USA

    Kai Kessenbrock & Zena Werb

  3. Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany

    Markus Krumbholz

  4. Nephrology Division, Medical Clinic I, University Hospital Großhadern, Munich, Germany

    Ulf Schönermarck

  5. Department of Pathology, Mannheim Clinics, University of Heidelberg, Mannheim, Germany

    Walter Back

  6. Department of Rheumatology, University of Lübeck, Vasculitis Center Universitaetsklinikum Schleswig-Holstein and Rheumaklinik Bad Bramstedt, Lübeck, Germany

    Wolfgang L Gross

  7. Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany

    Hermann-Josef Gröne

  8. Microscopy Core Facility, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, Germany

    Volker Brinkmann

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  1. Kai Kessenbrock
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  9. Dieter E Jenne
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Contributions

K.K. performed most of the experiments. M.K. performed IFN-α ELISA and contributed to data analysis and discussion. U.S., W.B. and W.L.G. provided patient material and clinical data. Z.W. provided critical input on data analysis. H.-J.G. provided kidney biopsies and clinical data. H.-J.G. and V.B. performed immunostainings and analysis of histology. K.K. and D.E.J. designed and supervised the study, analyzed data and wrote the manuscript. D.E.J. secured the funding. All authors discussed results and commented on the manuscript.

Corresponding authors

Correspondence to Kai Kessenbrock or Dieter E Jenne.

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Supplementary Text and Figures

Supplementary Figs. 1–7, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 821 kb)

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Kessenbrock, K., Krumbholz, M., Schönermarck, U. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15, 623–625 (2009). https://doi.org/10.1038/nm.1959

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