Role of Adaptive Immunity in the Development of Colitis in TLR5 Deficient Mice

炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)与 美国的健康负担。我们还知道，IBD患者的粘膜免疫反应对 肠道微生物区系。IBD的活跃症状与先天免疫有关，并被认为是由先天免疫介导的， 尤其是中性粒细胞渗入肠粘膜。相反，IBD的慢性期与 由黏膜维持，黏膜适应性免疫细胞的存在对CD4+T细胞具有特别重要的作用 细胞。最近的一些观察表明，这种与IBD相关的免疫反应的一个潜在原因可能是 调节先天免疫的基因突变。然而，目前还不清楚这种情况的主要后果是否 突变是指先天免疫功能的丧失或增强。鞭毛蛋白是鞭毛的单体亚基，是一种 肠道上皮细胞的主要天然免疫激活剂。我的CCFA研究奖学金试图定义 鞭毛蛋白先天免疫在小鼠肠道炎症模型中的作用。我们假设小鼠缺乏 鞭毛蛋白受体，Toll样受体5(TLR5)，可能对慢性炎症的发生有保护作用。相比之下， 我们观察到，缺乏TLR5的转基因小鼠会患上自发性结肠炎。我们假设TLR5KO结肠炎 由于无法控制共生微生物区系，导致TLR4和其他先天的激活 免疫信号通路。然而，我们最新的观察表明，这种变化不足以 使TLR5KO小鼠患上结肠炎。相反，我们初步观察到TLR5KO结肠炎与 这需要适应性免疫的改变。我们假设TLR5在肠道上皮细胞上的丢失导致 淋巴细胞获得了一种结肠炎的特征，它放大并维持由激活的 先天免疫力。或者，鉴于TLR5在抗原提呈细胞(APC)上的作用尚不明确， 越来越多的人意识到TLRs可以在T细胞上表达，我们还将考虑失去 APC和/或T细胞上的TLR5导致适应性免疫反应失调。我们建议对这些问题进行调查 通过检查TLR5K小鼠获得性免疫的变化并定义这些变化中的哪一个来进行假说 是必要的和/或足以引起结肠炎。除了促进对先天免疫的理解之外 肠道的相互作用，一个与IBD发病机制密切相关的区域，免疫学，我将从执行这些操作中学习 AIMS将极大地帮助我作为一名IBD研究人员的长期潜力。 相关性(请参阅说明)： 这项研究建议应阐明先天免疫缺陷小鼠适应性免疫的重要性。 结肠炎模型。它将阐明先天免疫和获得性免疫之间的串扰，最终 最终导致自发性结肠炎。

Inflammatory bowel diseases (IBD) Crohn's Disease (CD) and Ulcerative Colitis (UC) are associated with substantial health burden in the United States. It is also knownthat IBD patients have elevated mucosal immune responses to the enteric microflora. Active flares of IBD are associated with, and thought to be mediated by, innate immunity, specifically neutrophil infiltration to the intestinalmucosa. Conversely, the chronicphase of IBD is associated with, and maintained by, the increased mucosal presence of adaptive immune cells with a particularly important role for CD4+ T- cells. Several recent observations indicate that one underlying cause of such IBD-associated immune responses may be mutations in genes that mediate innate immunity. However, it is unclear whether the primary consequence of such mutations is loss or gain of innate immune function. Bacterial protein flagellin, the monomeric subunit of flagella, is a dominant innate immune activator of intestinal epithelial cells. My CCFA Research Fellowship sought to define the role of innate immunity to flagellin in murine models of gut inflammation. We hypothesized that mice lacking the flagellin receptor, toll-like receptor 5 (TLR5), might be protected from developing chronic inflammation. In contrast, we observed, that mice engineered to lack TLR5 develop spontaneous colitis. We hypothesize that TLR5KO colitis results from an inability to control the commensal microflora,which results in activation of TLR4 and other innate immune signaling pathways. However, our most recent observations suggest that such alterations are not sufficient to drive robust colitis in TLR5KO mice. Rather, we have preliminarily observed that TLR5KO colitis is associated with, and requires, alterations in adaptive immunity. We hypothesize that loss of TLR5 on gut epithelial cells results in lymphocytes acquiring a colitiogenic profile, which amplifies and sustains the inflammation triggered by activation of innate immunity. Alternatively, in light of the ambiguityregarding the role of TLR5 on antigen-presenting cells (APC) and increasing appreciation that TLRs can be expressed on T-cells, we will also consider the possibility that loss of TLR5 on APC and/or T-cells results in a dysregulated adaptive immune response. We propose to investigate these hypotheses by examining the alterations in adaptive immunity in TLR5K.Omice and defining which of these alterations are necessary and/or sufficient to drive colitis. In addition to advancing the understanding of innate-immune interactions in the gut, an area germane to the pathogenesis of IBD, the immunology, I will learn from executing these aims should greatly aid my long term potential as an IBD researcher. RELEVANCE (See instructions): This study proposed should delineate importance of adaptive immunity in innate immune deficient mouse colitis model. It will shed light on the crosstalk between innate and adaptive immunity that ultimately culminates in spontaneous colitis.