Nuclear structure in the development of lupus autoimmunity

描述（由申请人提供）：系统性红斑狼疮（SLE）被认为是由于对核自身抗原的耐受性丧失而导致的适应性免疫失败。在人类SLE患者和小鼠模型中，抗核抗体的存在是该疾病的诊断标准。尽管我们对SLE进展的理解有了重大进展，包括I型干扰素的关键作用，但对介导自身免疫发展的机制知之甚少。细胞凋亡的启动、执行或消退中的缺陷可诱导抗核抗体的产生。这表明在细胞凋亡过程中正确处理细胞核对于避免诱导异常免疫应答是必不可少的。核片段化涉及基因组DNA和核膜结构组分的裂解。在细胞凋亡期间裂解的核膜蛋白是核纤层蛋白B受体（LBR）。LBR通过结合染色质和核纤层来稳定核结构。LBR在人类中位于1 q42的SLEB 1狼疮易感区间内，在小鼠中位于同线区Sle 1、Nba-2、Swrl-1。该提案通过将有缺陷的Lbr基因引入到已建立的狼疮模型中，并通过分析LBR在狼疮易感小鼠品系中的表达，来测试LBR的破坏在狼疮自身免疫性发展中的作用。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is regarded as a failure of adaptive immunity due to a loss of tolerance to nuclear self-antigens. In human SLE patients and mouse models, the presence of anti-nuclear antibodies is a diagnostic criterion for the disease. Despite significant advances in our understanding of the progression of SLE, including the critical role of type I interferons, less is known of the mechanisms that mediate the development of autoimmunity. Defects in the initiation, execution or resolution of apoptosis can induce the development of anti-nuclear antibodies. This suggests that proper handling of the nucleus during apoptosis is essential to avoid induction of an aberrant immune response. Nuclear fragmentation involves cleavage of both genomic DNA and structural components of the nuclear envelope. A nuclear envelope protein cleaved during apoptosis is the Lamin B Receptor (LBR). The LBR stabilizes nuclear structure by binding both chromatin and the nuclear lamina. LBR located within the SLEB1 lupus susceptibility interval on 1q42 in humans, and in the syntenic regions Sle1, Nba-2, Swrl-1 in mice. This proposal tests the role of disruption of LBR in the development of lupus autoimmunity by introducing a defective Lbr gene into established models of lupus, and by analyzing the expression of LBR in lupus-prone mouse strains.