Mast Cell Function in Protective And Pathological Immunity: A Role for MDSC?

描述（由申请人提供）：肥大细胞是先天性和适应性免疫的关键激活剂。尽管肥大细胞在过敏性疾病中的作用最为人所知，但它们能迅速识别细菌和寄生虫病原体。IgE介导的信号传导是肥大细胞活化的最佳研究途径-我们显示的快速诱导Stat 5功能的途径。这种转录因子的缺失极大地破坏了肥大细胞的功能，包括迁移和细胞因子的产生。该提案将检验IgE介导的信号转导通过Fyn激酶介导的途径激活Stat 5并通过鞘氨醇激酶前馈增强的假设。我们还描述了一种新的肥大细胞和髓源性抑制细胞（MDSC）之间的相互作用，诱导MDSC产生炎性细胞因子，与这些细胞的普遍接受的作用相反。我们假设，Stat 3和Stat 5信号在MDSC是必需的这种效果，并支持理论，肥大细胞MDSC相互作用需要驱逐寄生虫日本圆线虫。我们的建议将测试的假设，肥大细胞和MDSC的相互作用控制保护性和病理性免疫，活动与Stat 5信号。我们将通过体外机制实验和体内功能测定来验证这一假设。我们的具体目标是：一。验证IgE通过鞘氨醇激酶增强的Fyn介导的途径激活Stat 5A和Stat 5 B的假设。二.验证肥大细胞调节MDSC功能的假说。!

DESCRIPTION (provided by applicant): Mast cells are critical activators of innate and adaptive immunity. Although best known for their role in allergic disease, mast cells rapidly recognize bacterial and parasitic pathogens. IgE-mediated signaling is the best-studied pathway for mast cell activation - a pathway we show rapidly induces Stat5 function. Loss of this transcription factor greatly disrupts mast cell functions, including migration and cytokine production. This proposal will test the hypothesis that IgE-mediated signaling activates Stat5 via a Fyn kinase-mediated pathway with feed-forward augmentation by sphingosine kinase. We also describe a novel interaction between mast cells and myeloid derived suppressor cells (MDSC) that induces MDSC to produce inflammatory cytokines, contrary to the commonly-accepted role of these cells. We postulate that Stat3 and Stat5 signaling in MDSC is required for this effect, and support the theory that mast cell-MDSC interactions are needed for expelling the parasite Nippostrongylus. Our proposal will test the hypothesis that mast cells and MDSC interactions control protective and pathological immunity, activities that are linked by Stat5 signaling. We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo. Our Specific Aims are: I. To test the hypothesis that IgE activates Stat5A and Stat5B through a Fyn-mediated pathway augmented by sphingosine kinase. II. To test the hypothesis that mast cells regulate MDSC function. !