Origins of specialized Mucosal Lymphocyte Subsets and Immunoglobulin Isotypes

描述（由申请方提供）：哺乳动物粘膜免疫系统是最大的淋巴区室，遇到最多样化的抗原负荷，并被全球绝大多数传染病破坏或感染。对小鼠和人的肠道相关淋巴组织（GALT）的研究提供了对专门的淋巴细胞亚群和免疫球蛋白（IG）同种型的更多了解，这些淋巴细胞亚群和免疫球蛋白同种型管理对食物抗原和药物的耐受性与对病原体的活化之间的平衡。然而，对GALT的比较免疫学知之甚少。这一点在产生这一系统的冷血脊椎动物中尤其如此。我建议测试的假设，专门的T细胞亚群和IG同种型在肠道是一个古老的和基本的一部分，我们的免疫系统是必要的早期历史的适应性免疫。鲨鱼和青蛙的GALT模型将检验这一假设。在鲨鱼中，肠道淋巴细胞的分子特征将集中在特殊亚群，如新的NAR-TcR T细胞的剧目。组织染色将在肠道上皮或固有层内解剖地映射这些细胞。第二个目标将采用非洲爪蛙系统的实验优势和免疫学工具，以调查哪些同种型和机制是保守的体液粘膜隔室。口服免疫将检测给药途径、类别转换的胸腺依赖性、外周口服耐受性的产生和轻链同种型功能。在低等脊椎动物中的GALT研究将告诉我们什么是介导防御和耐受的遗传学基础。此外，我们将深入了解适应性免疫系统的早期淋巴细胞亚群和剧目。 作为一名新的助理教授，我有足够的时间进行这项基础研究，三年后我的第一个R 01将有可能获得更强大的应用。这项工作将为我的独立职业生涯奠定基础，调查我们免疫系统的起源和自然历史，以更好地使医生能够修改剧目以改善疾病。NIAID战略计划的四个基石中的一个统一主题是需要更好地理解淋巴细胞调节，从自身免疫和过敏的剧目失败的极端，以及在模型原始脊椎动物中研究GALT免疫学的比较工作已经成熟，可以产生这样的理解。

DESCRIPTION (provided by applicant): The mammalian mucosal immune system is the largest lymphoid compartment, encounters the most diverse antigenic load, and is breached or infected by the great majority of infectious diseases worldwide. Studies of gut associated lymphoid tissues (GALT) in mouse and man have provided much insight into the specialized lymphocyte subsets and immunoglobulin (Ig) isotypes that manage the balance between tolerance to food antigens and commensals and activation against pathogen. However little is known of comparative immunology of GALT. This is especially true in the cold-blooded vertebrates where the system arose. I propose to test the hypothesis that specialized T cell subsets and Ig isotypes in the gut are an ancient and fundamental part of our immune system that were necessary early in the history of adaptive immunity. The shark and frog GALT are the models in which this hypothesis will be tested. In shark the molecular characterization of intestinal lymphocytes will focus on the repertoire of special subsets such as the new NAR-TcR T cell. Tissue staining will map these cells anatomically within the gut epithelia or lamina propria. The second aim will employ the experimental advantages and immunological tools of the African clawed frog system to investigate which isotypes and mechanisms are conserved in the humoral mucosal compartment. Oral immunizations will test route of administration, thymus dependence of class switch, generation of oral tolerance in the periphery and light chain isotype function. GALT study in lower vertebrates will teach us what is phylogenetically basic in mediating defense and tolerance. Additionally, we will gain insight into the early lymphocyte subpopulations and repertoires of the adaptive immune system. By allowing me protected time for this fundamental research as a new Assistant Professor, a stronger application will be possible for my first R01 in three years. This work will seed my independent career investigating the origins and natural history of our immune system to better able the physician to modify repertoires for the amelioration of disease. A unifying theme in the four cornerstones of NIAID's strategic plan is the need for a better comprehension of lymphocyte regulation from the extremes of failure of the repertoire to autoimmunity and allergy, and comparative work studying GALT immunology in model primitive vertebrates is ripe to yield such understanding.