A Novel Genetic Model of Systemic Lupus Erythematosus

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是产生抗核酸的自身抗体，最突出的是抗双链DNA(DsDNA)。DNA降解酶(DNase)清除细胞中DNA的缺陷与SLE的发病机制有关。我们已经确定了这样一种DNA酶的靶向缺失的小鼠的特征，并观察到它们表现出显著的抗dsDNA反应和其他SLE表现。因此，我们假设该小鼠品系代表了SLE的健壮的单基因模型。我们建议使用两个特定的目标来验证这个模型，并深入了解疾病的机制。在目标1中，我们将描述系统性红斑狼疮发展的动力学和特征，以及先天DNA传感通路的作用。在目标2中，我们将测试这种疾病的细胞学基础，特别是树突状细胞在破坏自身DNA耐受性方面的作用。总而言之，这些研究应该建立一种新的单基因动物模型，特别适合于实验性SLE的基因解剖。此外，他们还将验证SLE发病机制中的一种新的分子罪魁祸首，并表征其在核酸免疫耐受中的作用。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of autoantibodies against nucleic acids, most prominently against double-stranded DNA (dsDNA). Defective clearance of DNA from apoptotic cells by DNA-degrading enzymes (DNases) has been implicated into the pathogenesis of SLE. We have characterized mice with targeted deletion of one such DNase, and observed that they develop prominent anti-dsDNA reactivity and other SLE manifestations. We therefore hypothesize that this mouse strain represents a robust monogenic model of SLE. We propose to validate this model and gain insight into the mechanism of the disease, using two Specific Aims. In Aim 1, we will characterize the kinetics and features of SLE development, as well as the role of innate DNA-sensing pathways. In Aim 2, we will test the cellular basis of the disease, particularly the role of dendritic cells in the breach of tolerance to self-DNA. Collectively, thes studies should establish a novel monogenic animal model that would be particularly suitable for genetic dissection of experimental SLE. In addition, they would validate a novel molecular culprit in the pathogenesis of SLE and characterize its role in immune tolerance to nucleic acids.