BCAP regulation of pDC IFNa production in lupus

项目摘要 I型干扰素细胞因子家族促进系统性红斑狼疮的发生 它由许多不同的细胞对DNA和RNA做出反应。而免疫系统中的许多细胞 制造I型干扰素，浆细胞样树突状细胞(PDC)是一种特殊的细胞类型，可以产生 免疫复合体中大量的这些细胞因子对免疫复合体中的核酸的反应，而免疫复合体在系统性红斑狼疮中含量丰富。 在人类和小鼠的系统性红斑狼疮中，PDC被认为是重要的I型干扰素产生细胞 模特们。我们已经有了新的发现，信号适配器BCAP，它在 PDC是从这些细胞产生I型干扰素所必需的。此外，小鼠的BCAP缺乏 狼疮样疾病模型大大改善了疾病。因此，BCAP是一种潜在的治疗靶点。 SLE可减少PDC干扰素-α的产生。在这项建议中，我们进一步研究了BCAP在 PDC干扰素-α的产生和狼疮样疾病。我们将从两个方面探讨这一想法：1) 确定BCAP调节血浆细胞样树突状细胞I型干扰素产生的机制，以及2) 确定PDC中BCAP的表达是否促进狼疮样疾病。总之，这些实验将定义一个 体外和体内PDC I型干扰素产生的新调节机制。BCAP以前从未被 与PDC功能或SLE发病机制有关，因此我们的建议测试了专注于 确定BCAP在PDC中如何发挥作用，以及BCAP是否可能成为SLE的治疗靶点。

Project Summary The type I interferon (IFN) cytokine family promotes the development of systemic lupus erythematosus (SLE) and is made by many different cells in response to DNA and RNA. Whereas many cells of the immune system make type I interferon, plasmacytoid dendritic cells (pDC) are a specialized cell type that can produce large quantities of these cytokines in response to nucleic acids in immune complexes, which are abundant in SLE. pDC have been implicated as important type I interferon producing cells in SLE, both in humans and in mouse models. We have made the novel discovery that the signaling adapter BCAP, which is highly expressed in pDC, is required for type I interferon production from these cells. Additionally, deficiency in BCAP in a mouse model of lupus-like disease greatly ameliorates disease. Therefore, BCAP is a potential therapeutic target in SLE to reduce pDC interferon-alpha production. In this proposal, we further examine the function of BCAP in pDC interferon-alpha production and in lupus-like disease. We will explore this idea in two aims: 1) To determine the mechanism by which BCAP regulates plasmacytoid DC type I IFN production, and 2) To determine if BCAP expression in pDC promotes lupus-like disease. Together, these experiments will define a new regulatory mechanism for pDC type I IFN production in vitro and in vivo. BCAP has not previously been implicated in pDC function or in SLE pathogenesis, therefore our proposal tests novel hypotheses focused on determining how BCAP functions in pDC and whether BCAP may be a therapeutic target in SLE.