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

Manderson, Anthony P., Carlucci, Francesco, Lachmann, Peter J., Lazarus, Robert A ., Festenstein, Richard J, Cook, H. Terence, Walport, Mark J and Botto, Marina (2006) 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. Arthritis Research & Therapy, 8 3: 68-78. doi:10.1186/ar1936


Author Manderson, Anthony P.
Carlucci, Francesco
Lachmann, Peter J.
Lazarus, Robert A .
Festenstein, Richard J
Cook, H. Terence
Walport, Mark J
Botto, Marina
Title 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
Journal name Arthritis Research & Therapy   Check publisher's open access policy
ISSN 1478-6362
Publication date 2006-01-01
Sub-type Article (original research)
DOI 10.1186/ar1936
Open Access Status DOI
Volume 8
Issue 3
Start page 68
End page 78
Total pages 11
Place of publication London
Publisher Biomed Central Ltd
Language eng
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 overexpression 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 nontransgenic 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.
Keyword Rheumatology
Amyloid-p Component
Apoptotic Cells
Deoxyribonuclease-i
Igg Autoantibodies
Targeted Deletion
Circulating Dna
Cystic-fibrosis
Nzb/nzw Mice
Serum
Antibodies
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2007 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 15 Aug 2007, 19:21:19 EST