Nuclear structure in the development of lupus autoimmunity

描述(申请人提供)：系统性红斑狼疮(SLE)被认为是由于失去对核自身抗原的耐受性而导致的获得性免疫失败。在人类SLE患者和小鼠模型中，抗核抗体的存在是疾病的诊断标准。尽管我们对系统性红斑狼疮的进展有了很大的了解，包括I型干扰素的关键作用，但对调节自身免疫发展的机制知之甚少。在启动、执行或解决细胞凋亡的过程中存在缺陷，可导致抗核抗体的产生。这表明，在细胞凋亡过程中，对细胞核的适当处理对于避免诱导异常免疫反应至关重要。核碎裂包括基因组DNA和核膜结构成分的裂解。在细胞凋亡过程中被切割的核膜蛋白是Lamin B受体(LBR)。LBR通过结合染色质和核层来稳定核结构。人LBR位于SLEB1狼疮易感区间，小鼠LBR位于Sle1、NBA-2、Swrl-1共线区。这项建议通过将LBR基因缺陷的LBR基因导入已建立的狼疮模型，并通过分析LBR在狼疮易感小鼠品系中的表达，来测试LBR的干扰在狼疮自身免疫发展中的作用。

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.