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

适应性免疫在 TLR5 缺陷小鼠结肠炎发展中的作用

• 批准号: 8478091
• 负责人: MATAM VIJAY-KUMAR
• 金额: $ 2.43万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478091
• 关键词: Adoptive Transfer; Antigen-Presenting Cells; Area; B-Lymphocytes; Bacterial Proteins; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Chimera organism; Chronic; Chronic Phase; Colitis; Crohn' s disease; Data; Development; Diarrhea; Disease; Economics; Engineering; Enteral; Epithelial; Epithelial Cells; Exhibits; Fellowship; Flagella; Flagellin; Flare; Gastrointestinal Diseases; Genes; Health; Hematopoietic; Immune; Immune response; Immunology; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Instruction; Intestinal Mucosa; Intestines; Knock-out; Knockout Mice; Learning; Light; Lymphocyte; Measures; Mediating; Mentors; Modeling; Mucosal Immune Responses; Mus; Mutation; Natural Immunity; Neutrophil Infiltration; Pathogenesis; Patients; Population; Principal Investigator; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Role; Signal Pathway; Spleen; T-Lymphocyte; TLR4 gene; Tissues; Toll-Like Receptor 5; Ulcerative Colitis; United States; adaptive immunity; cost; innate immune function; intestinal epithelium; programs; receptor; social

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.

炎症性肠病 (IBD)、克罗恩病 (CD) 和溃疡性结肠炎 (UC) 与大量 美国的健康负担。众所周知，IBD 患者的粘膜免疫反应增强。 肠道微生物区系。 IBD 的活跃发作与先天免疫有关，并被认为是由先天免疫介导的， 特别是中性粒细胞浸润肠粘膜。相反，IBD 的慢性期与以下因素相关： 通过增加粘膜中适应性免疫细胞的存在来维持，其中 CD4+ T- 细胞发挥着特别重要的作用 细胞。最近的一些观察结果表明，这种 IBD 相关免疫反应的根本原因可能是 介导先天免疫的基因突变。然而，尚不清楚这种行为的主要后果是否是 突变是先天免疫功能的丧失或增强。细菌蛋白鞭毛蛋白是鞭毛的单体亚基，是一种 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 对鞭毛蛋白的先天免疫在小鼠肠道炎症模型中的作用。我们假设小鼠缺乏 鞭毛蛋白受体、Toll 样受体 5 (TLR5) 可能会受到保护，免于发生慢性炎症。相比之下， 我们观察到，缺乏 TLR5 的小鼠会出现自发性结肠炎。我们假设 TLR5KO 结肠炎 由于无法控制共生微生物群而导致 TLR4 和其他先天性微生物的激活 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 TLR5KO 小鼠中引起强烈的结肠炎。相反，我们初步观察到 TLR5KO 结肠炎与以下因素相关： 并需要适应性免疫的改变。我们假设肠上皮细胞上 TLR5 的缺失导致 淋巴细胞获得致结肠炎特征，从而放大并维持由激活的炎症引发的炎症 先天免疫。或者，鉴于 TLR5 对抗原呈递细胞 (APC) 的作用尚不明确 随着人们越来越认识到 TLR 可以在 T 细胞上表达，我们还将考虑 TLR 丢失的可能性 APC 和/或 T 细胞上的 TLR5 会导致适应性免疫反应失调。我们建议调查这些 通过检查 TLR5K.Omice 中适应性免疫的改变并定义这些改变中的哪些来提出假设 是驱动结肠炎所必需和/或充分的。除了增进对先天免疫的理解之外 肠道中的相互作用，这是与 IBD 发病机制、免疫学密切相关的领域，我将从执行这些过程中学习 目标应该极大地帮助我作为 IBD 研究人员的长期潜力。 相关性（参见说明）： 这项研究提出应该描绘先天免疫缺陷小鼠中适应性免疫的重要性 结肠炎模型。它将揭示先天免疫和适应性免疫之间的串扰，最终 最终导致自发性结肠炎。