LUPUS GENES AND B-CELL SIGNALING

描述（由申请人提供）：小鼠1号染色体上的Sle1和小鼠7号染色体上的Sle3代表了NZM2410小鼠模型中狼疮最强的两个位点。为了了解这些基因座是如何导致狼疮的，我们将这些疾病基因座作为遗传间隔回交到相对正常的C57BL/6背景上。而B6小鼠是健康的，B6。Sle1小鼠发展为轻度狼疮，而B6.Sle1。Sle3双基因小鼠发展为严重狼疮性肾炎。我们最近的研究表明，这些基因中的成熟b细胞表现出多种信号通路的渐进激活，包括AKT/mTOR轴、各种MAPK通路、NFkB、STAT3、STAT5和各种Bcl-2家族成员，激活水平与疾病严重程度和易感基因剂量密切相关。重要的是，其中一些轴的激活，特别是NFkB和STAT3，在患有严重狼疮的双基因小鼠中特别明显，但在B6中没有。Sle1老鼠。这些信号通路的激活是否对疾病是必要的或充分的尚不清楚。我们假设NFkB和STAT3的激活对狼疮的发病机制至关重要。这将在Aim 2和Aim 3中使用遗传方法和药理学方法进行测试。虽然Sle3的罪魁祸首基因仍然未知，但我们已经了解到Sle1中最强亚位点的候选基因，即SLAMF6/Ly108，以b细胞固有的方式发挥作用，破坏早期b细胞的耐受性。目前，Ly108破坏耐受性的分子机制尚不清楚。我们假设Ly108的多态性变异可能通过参与未成熟B细胞内不同的信号通路来破坏B细胞的耐受性。这一假设将在Aim 1中进行检验。总的来说，这些研究对系统性红斑狼疮的机制起源以及如何治疗具有重要意义。

DESCRIPTION (provided by applicant): Sle1 on murine chromosome 1 and Sle3 on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. To understand how these loci contribute to lupus, these disease loci have been backcrossed onto the relatively normal C57BL/6 background as congenic intervals. Whereas B6 mice are healthy, B6.Sle1 mice develop mild lupus, and B6.Sle1.Sle3 bicongenic mice develop severe lupus nephritis. We have recently documented that mature B-cells in these congenics exhibit progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MAPK pathways, NFkB, STAT3, STAT5, and various Bcl-2 family members, with the levels of activation correlating well with disease severity and susceptibility gene dosage. Importantly, the activation of some of these axes, notably NFkB and STAT3, were particularly pronounced in bicongenic mice with severe lupus, but not in B6.Sle1 mice. Whether the activation of any of these signaling pathways is necessary or sufficient for disease is not known. We hypothesize that NFkB and STAT3 activation is essential for the pathogenesis of lupus. This will be tested using a genetic approach in Aim 2 and a pharmacological approach in Aim 3. Though the culprit gene for Sle3 remains unknown, we have learned that the candidate gene for the strongest sub-locus within Sle1, namely SLAMF6/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Presently, the molecular mechanisms through which Ly108 might breach tolerance remain unclear. We hypothesize that polymorphic variants of Ly108 may breach B- cell tolerance by engaging different signaling pathways within immature B-cells. This hypothesis will be tested in Aim 1. Collectively, these studies have important implications towards the mechanistic origins o systemi lupus erythematosus and how it is managed therapeutically.