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

项目摘要 粘液表面容纳了大量的共生和共生细菌、病毒和其他微生物， 与宿主建立互惠互利的互动。这种微生物定植依赖于复杂的 与先天性和适应性免疫系统的相互作用，包括产生抗 肠道细菌抗原。有迫切需要了解适应性免疫反应如何 这些机制的失败如何导致炎症和免疫病理学。 最近的研究已经确定了B细胞中的toll样受体（TLR）信号传导在产生抗-IL-12中的需要。 免疫抗体。我们先前已经表明，细胞表面受体整合素αvβ3和组分 自噬途径的调节在B细胞中TLR信号传导以防止自身反应性细胞的过度扩张， 自身免疫在初步研究中，我们已经表明，B细胞特异性α v基因敲除小鼠（α v-CD 19小鼠） 增加肠内自发性生发中心的数量， 结肠炎基于这些数据，我们假设αvβ3调节B细胞对大肠杆菌的反应， 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，我们提出 为了验证这一假设：（1）测量α v-CD 19和对照中的抗人CD 19抗体和库 小鼠，以及细菌定植后的B细胞应答;（2）确定增加的机制 α v-CD 19小鼠对DSS结肠炎的易感性。这项研究非常重要，因为它将提供重要的见解 研究抗真菌抗体反应的调节机制，如果成功，将建立一个新的 将B细胞中失调的TLR信号传导与结肠炎易感性联系起来的范例。

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.