Beta-Defensins: Mediators of Gastrointestinal Inflammation

描述(申请人提供)：人体的防御系统可分为两个组成部分，先天免疫系统和获得性免疫系统。天然免疫系统是抵御入侵病原体(如细菌)的第一道防线，存在于植物和所有动物体内。这种反应非常迅速，但往往无法自行清除感染的病原体，因此，它向适应性免疫系统发出帮助的信号。适应性免疫系统非常特异，专门清除体内的外来病原体，但它的反应较慢，需要时间来发展。最终，入侵的病原体被免疫系统产生的炎症反应清除。然而，长期和过度活跃的炎症反应可能会对身体产生不利影响，就像炎症性肠病(IBD)一样。先天免疫系统通过称为Toll样受体(TLRs)的受体识别病原体的成分，从而检测外来病原体，如细菌。TLR位于特化细胞(树突状细胞和巨噬细胞)的表面，致病成分(激动剂)的结合导致它们被激活并释放信使分子(称为细胞因子)，从而进一步刺激先天和获得性免疫系统。先天免疫系统的其他组成部分是排列在胃和肠道内的上皮细胞。除了形成抵抗病原体入侵的物理屏障外，上皮细胞还分泌被称为β(2)-防御素的小蛋白，这种蛋白能够杀死细菌。最近，2-防御素被证明通过TLR依赖的机制激活树突状细胞和巨噬细胞，可能代表了天然免疫系统和获得性免疫系统之间的联系。以下提案中概述的项目的目标是确定2-防御素是否在胃肠道(GI)炎症过程中的炎症反应中起关键作用。因此，该项目涉及与胃肠道炎症发生有关的免疫方面和机制(即发病机制)。虽然在这些领域已经进行了大量的研究，但究竟是什么启动并导致了炎症反应的持续，还没有完全阐明。从IBD患者获得的证据表明，在活动期疾病期间，防御素显著增加。在胃肠道炎症的小鼠模型中也看到了类似的发现。我们将使用GI炎症的实验模型来表征和确定2-防御素在介导IBD的炎症机制中的作用。更具体地说，我们将(1)检测它们通过TLR4介导的途径激活树突状细胞和巨噬细胞并促进随后的促炎T细胞(获得性免疫)反应的能力，以及(2)确定缺乏特异性2-防御素Defb1的动物是否更容易患上胃肠道炎症。通过评估2-防御素激活免疫细胞的功能，我们将能够进一步确定慢性胃肠炎性疾病的发生/持续的潜在机制。通过增加我们对这些机制的理解，就有更大的潜力开发新的治疗方法来治疗这些疾病。公共卫生相关性：仅在美国，克罗恩病和溃疡性结肠炎等慢性胃肠道炎症性疾病就影响了100多万人。近年来，先天免疫系统及其组成部分在慢性胃肠道(GI)炎症中的作用日益明显，但其确切的参与性质仍有待充分阐明。这项拟议项目的最终目标是评估β-防御素(天然免疫系统的关键组成部分)在慢性胃肠道炎症发病机制中的作用。通过增加我们对胃肠道炎症致病机制中涉及的成分的了解和知识，就有了更大的潜力来开发新的治疗方法和治疗这些疾病。

DESCRIPTION (provided by applicant): The body's defense system can be divided into two components, the innate and adaptive immune systems. The innate immune system acts as the first line of defense against invading pathogens (e.g., bacteria) and is found in plants and all animals. The response is very rapid, but often is unable to clear the infecting pathogen by itself, and therefore, it signals the adaptive immune system to help. The adaptive immune system is very specific and specialized at eliminating foreign pathogens from the body, but its response is slower and requires time to develop. Eventually, the invading pathogen is removed by the inflammatory response generated by the immune system. However, a prolonged and overactive inflammatory response can have detrimental effects on the body, as is seen in inflammatory bowel disease (IBD). The innate immune system detects foreign pathogens, such as bacteria, by recognizing components of the pathogen via receptors, termed toll-like receptors (TLRs). TLRs are located on the surface of specialized cells (dendritic cells and macrophages) and binding of the pathogenic component (agonist) causes them to become activated and release messenger molecules (called cytokines) that further stimulate the innate and adaptive immune systems. Additional components of the innate immune system are the epithelial cells that line the stomach and intestines. In addition to forming a physical barrier to pathogen invasion, epithelial cells also secrete small proteins, termed beta (2)-defensins, which are capable of killing bacteria. Recently, 2-defensins have been shown to activate dendritic cells and macrophages by a TLR-dependent mechanism and may represent a link between the innate and adaptive immune system. The goal of project outlined in the following proposal is to determine if 2-defensins play a critical role in the inflammatory response seen during gastrointestinal (GI) inflammation. Thus the project deals with the immune aspects and mechanism (i.e., pathogenesis) involved in the generation of GI inflammation. Although a great deal of research has been conducted in these areas, what initiates and causes the inflammatory response to persist has not been fully clarified. Evidence obtained from IBD patients demonstrate that defensins are significantly increased during active disease. Similar findings have been seen in mouse models of GI inflammation. We will employ experimental models of GI inflammation to characterize and determine the role of 2-defensins in the inflammatory mechanism mediating IBD. More specifically, we will (1) examine their ability to activate dendritic cells and macrophages by a TLR4-mediated pathway and promote an ensuing pro- inflammatory T cell (adaptive immune) response and (2) determine if animals lacking a specific 2-defensin, Defb1, are more or less susceptible to gastrointestinal inflammation. By evaluating the function of 2-defensins to activate immune cells, we will be able to further define the potential mechanism involved in the generation/perpetuation of chronic GI inflammatory disorders. By increasing our understanding of these mechanisms, a greater potential exists to develop new therapies to treat these disorders. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis affect greater than 1 million people in the United States alone. In recent years, it has become increasingly apparent that the innate immune system and its components play a critical role in chronic gastrointestinal (GI) inflammation; however, the exact nature of their involvement remains to be fully elucidated. The ultimate goal of the proposed project is to evaluate the role of beta-defensins (key components of the innate immune system) in the pathogenesis of chronic gastrointestinal inflammation. By increasing our understanding and knowledge of components involved in the pathogenic mechanism of GI Inflammation, a greater potential exists to develop new therapies and treat these disorders.