Features of systemic lupus erythematosus in Dnase1-deficient mice

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease t hat affects over one million people in the United States. SLE is characteri zed by the presence of anti-nuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It is thought that the resulting immune comple xes accumulate in vessel walls, glomeruli and joints and cause a hypersensi tivity reaction type ill, which manifests as glomerulonephritis, arthritis and general vasculitis, The aetiology of SLE is unknown, but several studie s suggest that increased liberation or disturbed clearance of nuclear DNA-p rotein complexes after cell death may initiate and propagate the disease(1- 6). Consequently, Dnase1, which is the major nuclease present in serum, uri ne and secreta, may be responsible for the removal of DNA from nuclear anti gens at sites of high cell turnover and thus for the prevention of SLE (ref s 7-11). To test this hypothesis, we have generated Dnase1-deficient mice b y gene targeting. We report here that these animals show the classical symp toms of SLE. namely the presence of ANA, the deposition of immune complexes in glomeruli and full-blown glomerulonephritis in a Dnasel-dose-dependent manner. Moreover, in agreement with earlier reports(10), we found Dnase1 ac tivities 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 t he initiation of human SLE.