Isolated Lymphoid Follicle in Aging

说明(申请人提供)：免疫衰老是一种免疫功能失调的状态，导致老年人对感染的易感性增加，并有可能增加对自身免疫性疾病、慢性炎症性疾病和癌症的易感性。流行病学研究突显了粘膜免疫系统的免疫衰老的影响，这些研究证明，老年人因胃肠道感染而导致的死亡率显著增加，不适当的粘膜免疫反应的发生率增加，表现为70岁的人出现炎症性肠病的第二个高峰。导致粘膜免疫系统免疫衰老的机制在很大程度上尚不清楚。分离淋巴滤泡(ILF)是一种可诱导的有组织的肠道淋巴结构。在幼年动物中，这些结构作为诱导‘动态平衡’粘膜免疫反应的场所，包括产生抗原特异性IgA。本研究的假设是，由于对管腔刺激的炎症反应与年龄相关的变化，ILF的形成被增强和异常，导致保护性免疫受损，并易于产生不适当的粘膜免疫反应。 因此，在这项建议中，我们将研究ILF的异常形成和功能随年龄的变化。在具体目标1中，我们将使用UEA-I凝集素或抗B220染色的肠全层，免疫组织化学和流式细胞术来确定ILF的形成阶段(S)，并随着年龄的增加而增加。在特定目标2中，我们将使用定量聚合酶链式反应和流式细胞术来检测淋巴毒素、趋化因子和趋化因子受体的产生/表达，并将这些发现与先前发现的推动ILF形成特定阶段的因素的作用相关联。在特定目标1中，我们将使用免疫组织化学、扫描和电子显微镜、流式细胞术、细胞因子产生的体外细胞分析和体内免疫来研究ILF在衰老中的功能。这个项目的总体目标是了解器官这种特定的功能障碍是如何随着年龄的增长而产生的，并确定随着年龄的增长而增加的推动这种功能障碍的因素/步骤。未来的研究将试图以治疗性的方式操纵这一过程中的具体步骤。

DESCRIPTION (provided by applicant): Immunosenescence is a state of dysregulated immune function contributing to the increased susceptibility of the elderly to infection, and potentially to an increased susceptibility to autoimmune diseases, chronic inflammatory diseases, and cancer. The impact of immunosenescence of the mucosal immune system is highlighted by epidemiological studies that document a marked increase in mortality due to gastrointestinal infections in the elderly and an increased incidence of inappropriate mucosal immune responses as manifested by the 'second peak' of inflammatory bowel disease in individuals in their seventh decade of life. The mechanisms resulting in immunosenescence of the mucosal immune system are largely unexplored. Isolated lymphoid follicles (ILFs) are inducible organized intestinal lymphoid structures. In young animals these structures act as sites for the induction of 'homeostatic' mucosal immune responses including the production of antigen specific IgA. The hypothesis of this study is that as a consequence of age-related changes in the inflammatory response to luminal stimuli, ILF formation is augmented and aberrant resulting in impaired protective immunity and a predisposition toward inappropriate mucosal immune responses. Consequently we will examine the aberrant formation and function of ILFs with aging in this proposal. In specific aim 1 we will use intestinal whole mounts stained with UEA-I lectin or anti-B220, immunohistochemistry, and flow cytometry to define the stage(s) of ILF formation that are augmented with aging. In specific aim 2 we will examine the production/expression of lymphotoxin, chemokines, and chemokine receptors which have been identified to contribute to/drive ILF formation using quantitative PCR and flow cytometry and correlate these findings with the previously identified roles for these factors driving the specific stages of ILF formation found to be augmented in specific aim 1. In specific aim 3 we will use immunhistochemistry, scanning and electron microscopy, flow cytometry, and in vitro cellular assays of cytokine production, and in vivo immunization to examine the function of ILFs in aging. The overall goal of this project is to understand how organ this specific dysfunction arises with aging, and to identify the factors/steps which are augmented with aging that act to drive this dysfunction. Future studies will attempt to manipulate specific steps in this process in a therapeutic manner.