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Features of systemic lupus erythematosus in Dnase1-deficient mice

Nature Genetics volume 25, pages 177–181 (2000)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that affects over one million people in the United States. SLE is characterized by the presence of anti-nuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It is thought that the resulting immune complexes accumulate in vessel walls, glomeruli and joints and cause a hypersensitivity reaction type III, which manifests as glomerulonephritis, arthritis and general vasculitis. The aetiology of SLE is unknown, but several studies suggest that increased liberation or disturbed clearance of nuclear DNA-protein complexes after cell death may initiate and propagate the disease1,2,3,4,5,6. Consequently, Dnase1, which is the major nuclease present in serum, urine and secreta, may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover and thus for the prevention of SLE (refs 7–11). To test this hypothesis, we have generated Dnase1-deficient mice by gene targeting. We report here that these animals show the classical symptoms of SLE, namely the presence of ANA, the deposition of immune complexes in glomeruli and full-blown glomerulonephritis in a Dnase1-dose-dependent manner. Moreover, in agreement with earlier reports10, we found Dnase1 activities in serum to be lower in SLE patients than in normal subjects. Our findings suggest that lack or reduction of Dnase1 is a critical factor in the initiation of human SLE.

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Figure 1: Deletion of Dnase1 (ref. 12) by gene targeting.
Figure 2: ANA in Dnase1-deficient mice.
Figure 3: Immune-complex nephritis in Dnase1-deficient mice.
Figure 4: DNASE1 activity in sera of patients with nephropathic diseases.

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Acknowledgements

We thank B. Polzar for rat Dnase1 cDNA; P. Ferrier for the pPNT vector; E. Gau, E.-M. Konieczny, K. Klar, T. Klöckl and S. Wulf for technical assistance; and W. Zidek and M. Tepel for patient sera. This work was supported by a grant of the Fond der Chemischen Industrie to T.M.

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  1. Abteilung für Anatomie und Embryologie, Medizinische Fakultät, Ruhr-Universität Bochum, Bochum, Germany

    Markus Napirei, Harald Stephan & Hans Georg Mannherz

  2. Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Essen, Germany

    Holger Karsunky, Branko Zevnik & Tarik Möröy

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  1. Markus Napirei
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Correspondence to Tarik Möröy.

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Napirei, M., Karsunky, H., Zevnik, B. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 25, 177–181 (2000). https://doi.org/10.1038/76032

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