A Novel Genetic Model of Systemic Lupus Erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是产生针对核酸的自身抗体，最突出的是针对双链DNA（dsDNA）的自身抗体。DNA降解酶（DNA降解酶）对凋亡细胞DNA的清除缺陷与SLE的发病机制有关。我们的特点是有针对性地删除这样的DNA酶的小鼠，并观察到他们开发突出的抗dsDNA反应性和其他SLE表现。因此，我们假设这种小鼠品系代表了一种稳健的SLE单基因模型。我们建议使用两个特定目标来验证该模型并深入了解疾病的机制。在目标1中，我们将描述SLE发展的动力学和特征，以及先天DNA传感途径的作用。在目标2中，我们将测试疾病的细胞基础，特别是树突状细胞在破坏对自身DNA的耐受性中的作用。总之，这些研究将建立一种新的单基因动物模型，特别适合于实验性SLE的遗传解剖。此外，他们将验证一种新的分子罪犯在SLE的发病机制，并表征其在免疫耐受核酸的作用。

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.