Open Access Research article

The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus

Anthony P Manderson12, Francesco Carlucci1, Peter J Lachmann3, Robert A Lazarus4, Richard J Festenstein5, H Terence Cook6, Mark J Walport17 and Marina Botto1*

Author Affiliations

1 Rheumatology Section, Division of Medicine, Faculty of Medicine, Imperial College, London, UK

2 Institute of Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia

3 Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

4 Department of Protein Engineering, Genentech, Inc., CA, USA

5 Gene Control Mechanisms and Disease, Imperial College, London, UK

6 Department of Histopathology, Faculty of Medicine, Imperial College, London, UK

7 The Wellcome Trust, London, UK

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Arthritis Research & Therapy 2006, 8:R68  doi:10.1186/ar1936

Published: 10 April 2006

Abstract

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against ubiquitous antigens, especially nuclear components. Evidence makes it clear that the development of these autoantibodies is an antigen-driven process and that immune complexes involving DNA-containing antigens play a key role in the disease process. In rodents, DNase I is the major endonuclease present in saliva, urine and plasma, where it catalyses the hydrolysis of DNA, and impaired DNase function has been implicated in the pathogenesis of SLE. In this study we have evaluated the effects of transgenic over-expression of murine DNase I endonucleases in vivo in a mouse model of lupus. We generated transgenic mice having T-cells that express either wild-type DNase I (wt.DNase I) or a mutant DNase I (ash.DNase I), engineered for three new properties – resistance to inhibition by G-actin, resistance to inhibition by physiological saline and hyperactivity compared to wild type. By crossing these transgenic mice with a murine strain that develops SLE we found that, compared to control non-transgenic littermates or wt.DNase I transgenic mice, the ash.DNase I mutant provided significant protection from the development of anti-single-stranded DNA and anti-histone antibodies, but not of renal disease. In summary, this is the first study in vivo to directly test the effects of long-term increased expression of DNase I on the development of SLE. Our results are in line with previous reports on the possible clinical benefits of recombinant DNase I treatment in SLE, and extend them further to the use of engineered DNase I variants with increased activity and resistance to physiological inhibitors.