Genetic Dissection of B-Cell Signaling Pathways in Lupus

小鼠1号染色体上的Sle 1和小鼠7号染色体上的Sle S代表狼疮最强的2个基因座 在NZM 2410小鼠模型中。然而，正常（B6）的小鼠仅具有Sle 1，表现出轻度狼疮， 正常的小鼠被改造为携带这两个基因座，发展成严重的狼疮。因此，B6、B6.Sle1z和B6.Sle1z.Sle3z 同类菌株捕获了狼疮疾病发展的3个不同阶段，使人联想到 人类狼疮发展。最近，我们已经证明，这些小鼠中的B细胞表现出一种 多种信号通路的进行性激活，包括AKT/mTOR轴，各种MARK 途径，NFkB，STATS和STATS，以及各种Bcl-2家族成员，与活化水平 与疾病严重程度相关。我们还了解到，最强亚- Slelz内的基因座SLAM/Ly 108以B细胞内在方式发挥功能，破坏早期B细胞耐受性。 虽然SleSz的致病基因尚不清楚，但很明显，SleSz影响了DC的功能 和B细胞之间的联系基于这些观察，我们提出了三个目标。 目标1。为了确定Slelz B细胞中上调的信号通路是否是 自身抗原的慢性刺激和/或正常和狼疮之间的多态性差异， Ly 108的相关等位基因/同种型。我们会确定慢性BCR刺激，以及狼疮- 相关的Ly108.1和Sle 1b/SLAM的“正常”Ly108.2同种型可能有助于信号传导。 在Slelz B细胞中观察到的指纹。 目标2.为了区分B细胞内在与DC依赖性分子机制， 而SleSz可能有助于狼疮中的B细胞活化。除了确定SleSz如何影响B细胞外， 信号内在，我们也将阐明细胞和分子机制，可以解释为什么 狼疮树突状细胞可能更善于“帮助”B细胞产生自身抗体。 目标3。为了确定AKT轴或STATS（或其他轴， 其中指出）是B6.SleIz.SleSz小鼠中所见狼疮表型所必需的。通过消融或超- 表达这些分子在B细胞内在的方式，我们将确定如何激活这2个 B6. Slez. SleSz同源小鼠中B细胞中的通路可能导致狼疮。

Sle1 on murine chromosome 1 and SleS on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. Whereas normal (B6)mice engineered to have Sle1 alone exhibit mild lupus, normal mice engineered to bear both loci develop severe lupus. Hence, B6, B6.Sle1z and B6.Sle1z.Sle3z congenic strains capture 3 distinct stages of disease development in lupus, reminiscent of the stages seen in human lupus development. More recently, we have documented that B-cells in these mice exhibit a progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MARK pathways, NFkB, STATS and STATS, and various Bcl-2 family members, with the levels of activation correlating well with disease severity. We have also learned that the candidate gene for the strongestsub- locus within Slelz, SLAM/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Though the culprit genes for SleSz remain unknown, it is apparent that SleSz impacts the function of DCs and B-cells intrinsically. Based on these observations, we propose 3 Aims. Aim 1. To ascertain if the signaling pathways upregulated in Slelz B-cells are the direct consequence of chronic stimulation by autoantigens and/or polymorphic differences between the normal and lupus- associated alleles/isoforms of Ly108. We will ascertain how chronic BCR stimulation, as well as the lupus- associated Ly108.1 and the "normal" Ly108.2 isoforms of Sle1b/SLAM, might contribute to the signaling fingerprints observed in Slelz B-cells. Aim 2. To distinguish between the B-cell intrinsic versus DC-dependent molecular mechanisms through which SleSz might contribute to B-cell activation in lupus. In addition to determining how SleSz affects B-cell signaling intrinsically, we will also elucidate the cellular and molecular mechanisms that may explain why lupus DCs may be better at "helping" B-cells makeautoantibodies. Aim 3. To ascertain the degree to which B-cell intrinsic activation of the AKT axis, or STATS (or other axes, where indicated) is necessary for the lupus phenotypes seen in B6.Slelz.SleSz mice. By ablating or hyper- expressing these molecules in a B-cell intrinsic fashion, we will ascertain how the activation of these 2 pathways in B-cells might contribute to lupus in B6.Slelz.SleSz congenic mice.