Regulation of TLR signaling in anti-commensal B cell responses and mucosal inflammation

项目摘要 粘膜表面有许多共生和共生的细菌、病毒和其他微生物，它们 与主人建立互惠互利的互动关系。这种微生物的定植依赖于复合体 与先天免疫系统和适应性免疫系统的相互作用，包括产生针对 共生细菌抗原。迫切需要了解适应性免疫反应是如何 共生体是受调控的，以及这些机制的失败如何导致炎症和免疫病理。 最近的研究发现，在B细胞中需要Toll样受体(TLR)信号来产生抗- 共生抗体。我们先前已经证明了细胞表面受体整合素αvβ3及其组件 自噬途径调节B细胞中的TLR信号，以防止自身反应细胞过度扩张 自身免疫力。在初步研究中，我们已经证明了B细胞特异性αv基因敲除小鼠(αv-CD19小鼠)具有 增加肠道中自发生发中心的数量，更容易受到炎症的影响 结肠炎。基于这些数据，我们假设αvβ3调节B细胞对共生菌的反应，以 保持对感染的防御，但防止过度活跃的炎症反应。在本申请中，我们建议 为了验证这一假设：(1)测量αv-CD19和对照的抗共生抗体和谱系 小鼠，并跟随细菌定植后的B细胞反应；(2)确定增加的机制 αv-CD19小鼠对dss结肠炎的易感性。这项研究具有非常重要的意义，因为它将提供重要的见解 研究抗共生抗体反应的调节机制，如果成功，将建立一个新的 B细胞中异常调节的TLR信号与结肠炎易感性之间的联系。

Project Summary Mucosal surfaces house numerous commensal and symbiotic bacteria, viruses and other microorganisms, which establish mutually beneficial interactions with their host. This microbial colonization relies on complex interactions with the innate and adaptive immune systems, including the generation of antibodies against commensal bacteria antigens. There is a pressing need to understand how adaptive immune responses to commensals are regulated, and how failure of these mechanisms lead to inflammation and immune pathology. Recent studies have identified a requirement for toll-like receptor (TLR) signaling in B cells in generating anti- commensal antibodies. We have previously shown that the cell surface receptor integrin αvβ3 and components of the autophagy pathway regulate TLR signaling in B cells to prevent overexpansion of autoreactive cells and autoimmunity. In preliminary studies, we have shown that B cell-specific αv-knockout mice (αv-CD19 mice) have increase numbers of spontaneous germinal centers in the intestine and are more susceptible to inflammatory colitis. Based on these data, we hypothesize that αvβ3 regulates B cell responses to commensal bacteria to maintain defense against infection but prevent overactive inflammatory responses. In this application we propose to test this hypothesis by: (1) measuring anti-commensal antibodies and repertoires in αv-CD19 and control mice, and following B cell responses after bacterial colonization; (2) determining the mechanism of increased susceptibility to DSS colitis in αv-CD19 mice. This research is highly significant as it will provide important insights into mechanisms of regulation of anti-commensal antibody responses, and if successful, will establish a new paradigm linking dysregulated TLR signaling in B cells to susceptibility to colitis.