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

描述（由申请人提供）： 在美国，炎症性肠病（IBD）、克罗恩病（CD）和溃疡性结肠炎（UC）与大量健康负担相关。还已知IBD患者对肠道微生物菌群具有升高的粘膜免疫应答。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肠粘膜。相反，IBD的慢性期与适应性免疫细胞的粘膜存在增加有关，并由其维持，其中CD 4 + T细胞具有特别重要的作用。最近的一些观察表明，这种IBD相关免疫反应的一个潜在原因可能是介导先天免疫的基因突变。然而，目前还不清楚这种突变的主要后果是先天免疫功能的丧失还是获得。鞭毛蛋白是鞭毛的单体亚单位，是肠上皮细胞的主要天然免疫激活因子。我的CCFA研究奖学金旨在确定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，缺乏鞭毛蛋白受体，toll样受体5（TLR 5）的小鼠可能会受到保护，不会发生慢性炎症。相反，我们观察到，[原文如此]缺乏TLR 5的小鼠会发生自发性结肠炎。我们假设TLR 5 KO结肠炎是由于无法控制肠道微生物菌群，从而导致TLR 4和其他先天免疫信号通路的激活。然而，我们最近的观察表明，这种改变不足以驱动TLR 5 KO小鼠中的稳健结肠炎。相反，我们已经初步观察到TLR 5 KO结肠炎与适应性免疫的改变相关，并且需要适应性免疫的改变。我们推测，肠道上皮细胞上TLR 5的缺失导致淋巴细胞获得结肠炎原性特征，其放大并维持由先天免疫激活引发的炎症。或者，鉴于TLR 5在抗原呈递细胞（APC）上的作用的不明确性以及对TLRs可以在T细胞上表达的认识的增加，我们还将考虑APC和/或T细胞上TLR 5的丧失导致失调的适应性免疫应答的可能性。我们建议通过检查TLR 5 KO小鼠适应性免疫的改变来研究这些假设，并确定这些改变中哪些是必要的和/或足以驱动结肠炎。除了推进对肠道中先天免疫相互作用的理解，这是一个与IBD发病机制密切相关的领域，免疫学，我将从执行这些目标中学习，这将极大地帮助我作为IBD研究人员的长期潜力。 公共卫生相关性：本研究提出[原文如此]应描述先天免疫缺陷小鼠结肠炎模型中适应性免疫的重要性。它将阐明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。

DESCRIPTION (provided by applicant): 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 known that 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 intestinal mucosa. Conversely, the chronic phase 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, [sic] 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 ambiguity regarding 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 TLR5KO mice 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. PUBLIC HEALTH RELEVANCE: This study proposed [sic] 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.