Features of systemic lupus erythematosus in Dnase1-deficient mice
Features of systemic lupus erythematosus in Dnase1-deficient mice
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DOI：
10.1038/76032
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发表时间：
2000-06-01
期刊：
影响因子：
30.8
通讯作者：
Möröy, T
中科院分区：
文献类型：
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作者：
Napirei, M;Karsunky, H;Möröy, T
系统性红斑狼疮（SLE）是一种多因素自身免疫性疾病，在美国影响超过一百万人。SLE的特征在于存在针对裸DNA和整个核小体的抗核抗体（ANA）。据认为，产生的免疫复合物在血管壁、肾小球和关节中积累，并引起III型超敏反应，其表现为肾小球肾炎、关节炎和全身性血管炎。SLE的病因尚不清楚，但一些研究表明，细胞死亡后核DNA-蛋白质复合物的释放增加或清除紊乱可能引发并传播疾病（1-6）。因此，血清、尿液和分泌物中存在的主要核酸酶Dnase 1可能负责从细胞高周转位点的核抗原中去除DNA，从而预防SLE（参考文献7-11）。为了验证这一假设，我们通过基因靶向产生了Dnase 1缺陷小鼠。我们在这里报告，这些动物表现出典型的SLE症状。即ANA的存在、免疫复合物在肾小球中的沉积和以Dnasel剂量依赖性方式的完全发展的肾小球肾炎。此外，与早期报道一致（10），我们发现SLE患者血清中的Dnase 1活性低于正常受试者。我们的研究结果表明，缺乏或减少Dnase 1是一个关键因素，在人类SLE的启动。
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 ill, 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 disease(1-6). 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 7-11). 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 Dnasel-dose-dependent manner. Moreover, in agreement with earlier reports(10), 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.