BCAP regulation of TLR7/9 signaling in Lupus

项目总结 系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病，其特征是 循环中的针对核酸和与之相关的蛋白质的自身抗体。通过 TLR7和TLR9是TLR7和TLR9的核酸感受器，它们在SLE的发病机制中起着关键作用，并且TLR信号失控 可以在人类和小鼠模型中促进狼疮的发生。浆细胞样树突状细胞和B细胞 表达这些核酸敏感的TLR，在SLE的发病机制中起重要作用。自身反应性B细胞产生 SLE中的致病自身抗体和B细胞抗体的产生受TLR7和TLR9信号的促进。 PDC使用TLR7和TLR9对免疫复合体中的核酸进行反应，导致大量 I型干扰素细胞因子的数量，它对免疫反应具有多效性，包括增强 树突状细胞(DC)成熟、浆细胞形成和T细胞反应，所有这些都可以促进饲料 免疫激活的前向环。因此，了解TLR7和TLR9 在这两种关键细胞类型中调节信号转导对于理解SLE的发病机制很重要 以及确定这种疾病的治疗目标。我们已经确定了信号适配器B细胞适配器 PI3-激酶(BCAP)在多种免疫谱系中作为TLR信号的关键调节器。首先，我们发现在 巨噬细胞BCAP通过激活PI3-激酶抑制TLR诱导的炎性细胞因子的产生。我们 最近发现BCAP促进PDC干扰素α的分泌，但不促进IL-6的分泌。我们也已经开始研究如何 BCAP调节B细胞TLR7/9的反应，这是一个研究较少的领域。我们的初步数据显示，BCAP是一种 B细胞TLR7/9的关键调节因子在所有B细胞亚群中的反应，尤其是在 脾边缘带B细胞的增殖和免疫球蛋白分泌。此外，我们还发现BCAP- 缺乏保护TLR7.1小鼠狼疮模型免受疾病的影响。总而言之，我们的发现显示了一个重要的 BCAP在PDC和B细胞内体TLR信号转导中的作用，两者在SLE的发病机制中都很重要。给定 TLR7和TLR9信号在SLE B细胞和PDC中的重要性，这一应用的前提是 BCAP对PDC和B细胞TLR7/9信号的调控在狼疮样疾病的发生发展中起关键作用。 具体地说，我们将1)确定BCAP调节TLR7/9诱导的干扰素α产生的机制 PDCs，2)确定BCAP调节B细胞TLR7/9反应的机制，以及3)确定 用两种小鼠模型研究pDC和B细胞中BCAP在狼疮样疾病中的相对作用。

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the nucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling. pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9 signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE and in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter for PI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that in macrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. We recently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine how BCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is a key regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease in proliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP- deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an important role of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given the importance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is that BCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease. Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production in pDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine the relative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.