Features of systemic lupus erythematosus in Dnase1-deficient mice

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 711). 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.

References

  1. 1

    Carroll, M.C. The lupus paradox. Nature Genet. 19, 3– 4 (1998).

  2. 2

    Vanholder, R., De Keyser, F., Kips, J., Praet, M. & Naeyaert, J.M. The pathophysiology of lupus erythematosus. Eur. J. Dermatol. 1, 4–7 (1998).

  3. 3

    Berden, J.H.M., Licht, R., Van Bruggen, M.C.J. & Tax, W.J.M. Role of nucleosomes for induction and glomerular binding of autoantibodies in lupus nephritis. Curr. Opin. Nephrol. Hypertens. 8, 299–306 (1999).

  4. 4

    Rosen, A. & Casciola-Rosen, L. Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease. Cell Death Differ. 6, 6– 12 (1999).

  5. 5

    Eilat, D. & Naparstek, Y. Anti-DNA autoantibodies: a puzzle of autoimmune phenomena. Immunol. Today 20, 339–342 (1999).

  6. 6

    Lachmann, P.J. An attempt to characterize the lupus erythematosus cell antigen. Immunology 4, 153–163 ( 1961).

  7. 7

    Lacks, S.A. Deoxyribonuclease I in mammalian tissues. J. Biol. Chem. 256, 2644–2648 (1981).

  8. 8

    Takeshita, H. et al. Mouse deoxyribonuclease I (Dnase I): biochemical and immunological characterization, cDNA structure and tissue distribution. Biochem. Mol. Biol. Int. 42, 65–75 (1997).

  9. 9

    Peitsch, M.C., Polzar, B., Tschopp, J. & Mannherz, H.G. About the involvement of deoxyribonuclease I in apoptosis. Cell Death Differ. 1, 1–6 (1994).

  10. 10

    Chitrabamrung, S., Rubin, R.L. & Tan, E.M. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol. Int. 1, 55–60 (1981).

  11. 11

    Macanovic, M. & Lachmann, P.J. Measurement of deoxyribonuclease I (DNase) in the serum and urine of systemic lupus erythematosus (SLE)-prone NZB/NZW mice by a new radial enzyme diffusion assay. Clin. Exp. Immunol. 108, 220–226 ( 1997).

  12. 12

    Peitsch, M.C., Irmler, M., French, L.E. & Tschopp, J. Genomic organisation and expression of mouse deoxyribonuclease I. Biochem. Biophys. Res. Commun. 207, 62–68 (1995).

  13. 13

    Shimoda, M. et al. Anti-DNA IgA autoantibodies are spontaneously generated in mouse Peyer's patches. Immunology 95, 200 –207 (1998).

  14. 14

    Polzar, B. et al. Distribution of deoxyribonuclease I in rat tissues and its correlation to cellular turnover and apoptosis (programmed cell death). Eur. J. Cell Biol. 64, 200–210 (1994).

  15. 15

    Rumore, P.M. & Steinman, C.R. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J. Clin. Invest. 86, 69– 74 (1990).

  16. 16

    Macanovic, M. et al. The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243–252 (1996).

  17. 17

    Verthelyi, D., Dybdal, N., Elias, K.A. & Klinman, D.M. DNAse treatment does not improve the survival of lupus prone (NZB/NZW) F1 mice . Lupus 7, 223–230 (1998).

  18. 18

    Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19, 56–59 (1998).

  19. 19

    Bickerstaff, M.C.M. et al. Serum amyloid P component controls chromatin degradation and prevents anti-nuclear autoimmunity. Nature Med. 5, 694–697 (1999).

  20. 20

    Davis, J.C. et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68– 76 (1999).

  21. 21

    Nadano, D., Yasuda, T. & Kishi, K. Measurement of deoxyribonuclease 1 activity in human tissues and body fluids by a single radial enzyme-diffusion method. Clin. Chem. 39, 448–452 ( 1993)

  22. 22

    Elkon, K.B., Parnassa, A.P. & Foster, C.L. Lupus autoantibodies target ribosomal P proteins. J. Exp. Med. 162, 459–471 (1985).

  23. 23

    Moore, T.L., Weiss, T.D., Neucks, S.H., Baldassare, A.R. & Zuckner, J. Extractable nuclear antigens. Semin. Arthritis Rheum. 10, 309–318 (1981).

  24. 24

    Polzar, B. & Mannherz, H.G. Nucleotide sequence of a full length cDNA clone encoding the deoxyribonuclease I from the rat parotid gland . Nucleic Acids Res. 18, 7151 (1990).

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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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Correspondence to Tarik Möröy.

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