Origins of specialized Mucosal Lymphocyte Subsets and Immunoglobulin Isotypes

描述(申请人提供)：哺乳动物的粘膜免疫系统是最大的淋巴系统，遇到最多样化的抗原负载，并被世界上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)的研究提供了对特殊的淋巴细胞亚群和免疫球蛋白(Ig)亚型的深入了解，这些亚群和免疫球蛋白(Ig)亚型管理着对食物抗原和共生体的耐受与对病原体的激活之间的平衡。然而，对高尔特的比较免疫学知之甚少。在该系统产生的冷血脊椎动物中尤其如此。我建议检验这样一种假设，即肠道中专门的T细胞亚群和免疫球蛋白同型是我们免疫系统的一个古老和基本的部分，在适应性免疫的历史早期是必要的。鲨鱼和青蛙高尔特是检验这一假说的模型。在鲨鱼中，肠道淋巴细胞的分子特征将集中在特殊亚群的谱系上，例如新的NAR-TCRT细胞。组织染色将这些细胞解剖地定位在肠上皮或固有层内。第二个目标将利用非洲爪蛙系统的实验优势和免疫学工具来研究体液粘膜中哪些同型和机制是保守的。口服免疫将测试给药途径、胸腺依赖类开关、外周口服耐受性的产生和轻链同型功能。对低等脊椎动物的高尔特研究将告诉我们什么是调节防御和耐受的系统发育基础。此外，我们还将深入了解适应性免疫系统的早期淋巴细胞亚群和谱系。 通过允许我作为新的助理教授有保护的时间进行这项基础研究，我将有可能在三年后的第一个R01中获得更强大的应用。这项工作将为我的独立职业生涯奠定基础，我将研究我们免疫系统的起源和自然历史，以便更好地使医生能够为改善疾病而修改曲目。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，从谱系失效到自身免疫和过敏的极端情况，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.