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

Systemic lupus erythematosus (SLE) is a disease characterized by the production of a variety of auto-antibodies against ubiquitous intracellular and cell surface antigens. Detailed analysis of these autoantibodies by many researchers has revealed several key findings. First, nuclear antigens are prominent with anti-double-stranded DNA (dsDNA) and anti-nucleosome antibodies extremely common in SLE patients (reviewed in [1]). Second, immune complexes containing these autoantibodies and nucleosomes are thought to mediate pathology following their localization in tissues [2-4]. Third, the anti-nuclear antibodies demonstrate all the hallmarks of an antigen-driven, T-cell dependent mechanism [5]. The antibodies are of high affinity, have undergone isotype switching and show evidence of somatic mutation and epitope spreading [6].Accumulating evidence suggests that inefficient clearance of apoptotic cells provide the source of the nuclear antigens driving the development of autoimmunity. The autoantigens targeted in SLE have been shown to cluster in and on the surface blebs of apoptotic cells [7,8] and ablation in mice of a number of genes whose products mediate the clearance of apoptotic cells, such as C1q [9,10], secreted IgM [11,12], cMer [13,14] and transglutaminase 2 [15,16] is associated with the development of a lupus-like disease.DNase I catalyses the hydrolysis of dsDNA, whether free or as part of a nucleosome, and is the major endonuclease present in saliva, urine and plasma in mice [17,18]. Impaired DNase I function has been implicated in the pathogenesis of SLE for many years since the initial observation that DNase activity is low in the serum of patients with SLE [19] and in lupus-prone NZB/NZW mice [20]. The reduced DNase I activity in SLE patients also correlates with an increased serum concentration of globular actin (G-actin), a potent inhibitor of DNase [19,21]. Mutations in Dnase1 have been identified in two Japanese SLE patients, resulting in low DNase