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）与大量的肠内炎症相关。 美国的健康负担。还已知IBD患者对免疫球蛋白的粘膜免疫应答升高， 肠道微生物区系IBD的活动性发作与先天免疫相关，并被认为是由先天免疫介导的， 特别是中性粒细胞浸润到尿道粘膜。相反，IBD的慢性期与 维持，增加粘膜存在的适应性免疫细胞与特别重要的作用，为CD 4 + T- 细胞最近的一些观察表明，这种IBD相关免疫应答的一个潜在原因可能是 介导先天免疫的基因突变。然而，目前尚不清楚这种情况的主要后果是否是 突变是先天免疫功能的丧失或获得。细菌蛋白鞭毛蛋白是鞭毛的单体亚基，是一种蛋白质， 肠上皮细胞的显性先天免疫激活剂。我的CCFA研究奖学金试图定义 先天免疫在肠道炎症小鼠模型中对鞭毛蛋白的作用我们假设， 鞭毛蛋白受体Toll样受体5（TLR 5）可能被保护免于发生慢性炎症。与此相反， 我们观察到，经工程改造缺乏TLR 5的小鼠发生自发性结肠炎。我们假设TLR 5 KO结肠炎 由于无法控制肠道微生物菌群，导致TLR 4和其他先天性 免疫信号通路然而，我们最近的观察表明，这种改变不足以 在TLR 5 KO小鼠中驱动强烈的结肠炎。相反，我们已经初步观察到TLR 5 KO结肠炎与， 需要适应性免疫的改变我们假设肠道上皮细胞上TLR 5的缺失导致了 淋巴细胞获得结肠炎的概况，放大和维持炎症触发激活 先天免疫另外，鉴于TLR 5在抗原呈递细胞（APC）中的作用尚不明确， 以及越来越多的人认识到TLR可以在T细胞上表达，我们也将考虑TLR的丧失可能性。 APC和/或T细胞上的TLR 5导致失调的适应性免疫应答。我们建议调查这些 通过检查TLR5K.0小鼠中获得性免疫的改变并确定这些改变中的哪一种， 是导致结肠炎的必要条件和/或充分条件除了推进对先天免疫的理解， 肠道中的相互作用，一个与IBD发病机制密切相关的领域，免疫学，我将从执行这些 目标应该大大有助于我作为IBD研究人员的长期潜力。 相关性（参见说明）： 本研究提示，获得性免疫在先天免疫缺陷小鼠中的重要性 结肠炎模型。它将揭示先天免疫和适应性免疫之间的相互作用， 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.