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)与巨大的健康负担有关。众所周知，IBD患者对肠道微生物区系的黏膜免疫反应增强。IBD的活动性发作与先天免疫有关，并被认为是由其介导的，尤其是中性粒细胞对肠粘膜的渗透。相反，IBD的慢性期与黏膜适应性免疫细胞的增加有关，并由其维持，而黏膜适应性免疫细胞对CD4+T细胞具有特别重要的作用。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介导先天免疫的基因突变。然而，目前尚不清楚这种突变的主要后果是先天免疫功能的丧失还是增强。鞭毛蛋白是鞭毛的单体亚基，是肠道上皮细胞的主要天然免疫激活剂。我的CCFA研究奖学金试图确定对鞭毛蛋白的先天免疫在小鼠肠道炎症模型中的作用。我们假设，缺乏鞭毛蛋白受体Toll样受体5(TLR5)的小鼠可能会受到保护，免受慢性炎症的影响。相反，我们观察到，[原文如此]被设计为缺乏TLR5的小鼠患上自发性结肠炎。我们假设TLR5KO结肠炎是由于无法控制共生微生物群而导致TLR4和其他先天性免疫信号通路的激活。然而，我们最新的观察表明，这种变化不足以推动TLR5KO小鼠患上结肠炎。相反，我们已经初步观察到TLR5KO结肠炎与获得性免疫改变有关，并且需要改变。我们假设，肠道上皮细胞上TLR5的丢失导致淋巴细胞获得结肠炎的特征，这种特征放大并维持由天然免疫激活引发的炎症。或者，鉴于TLR5在抗原提呈细胞(APC)上的作用尚不明确，以及对TLRs可在T细胞上表达的认识日益增强，我们还将考虑TLR5在APC和/或T细胞上的缺失导致适应性免疫反应失调的可能性。我们建议通过检测TLR5KO小鼠获得性免疫的变化来研究这些假设，并确定这些变化中的哪些是必要的和/或足以驱动结肠炎。除了促进对肠道天然免疫相互作用的理解，肠道是与IBD发病机制密切相关的一个领域，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一名IBD研究人员的长期潜力。 公共卫生相关性：这项研究建议[原文如此]应阐明适应性免疫在先天免疫缺陷小鼠结肠炎模型中的重要性。它将揭示先天性免疫和获得性免疫之间的串扰，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.