Innate immune regulation of inflammation and adaptive immunity

描述（由申请人提供）：近年来，先天免疫已经从“免疫学家的肮脏的小秘密”成为免疫学中最活跃和最令人兴奋的领域之一。脊椎动物先天免疫细胞的许多识别分子已被确定，现在对它们的作用机制也有了很多了解。尽管如此，在我们真正了解如何利用这些机制进行疫苗接种和癌症免疫治疗或如何阻断它们来治疗自身免疫性和炎症性疾病之前，还有很多东西要学。这个拟议的计划项目结合了4名在先天免疫领域具有成熟专业知识的研究人员，以追求他们独立研究工作的相关研究，但包含许多联系和联合努力的巨大潜力。在项目#1中，DeFranco博士将利用他新创建的myd 88条件等位基因来剖析Toll样受体信号传导的细胞基础，以全身和粘膜免疫应答为重点，重点是气道和真菌感染。在项目#2中，马博士将分析泛素修饰调节剂A20在树突状细胞中抑制TLR反应和预防炎症性疾病的作用。在项目#3中，Lowell博士将确定髓样细胞在Lyn-deficient小鼠模型中促进狼疮样自身免疫的机制。最后，在项目#4中，Locksley博士将确定几丁质（一种在真菌和无脊椎动物中发现的多糖）如何促进2型免疫，以及它如何与TLR信号通路相互作用以调节免疫反应的类型。Lay语言：免疫系统识别病毒，细菌，真菌和多细胞无脊椎动物的保守元素，使其能够检测感染并对抗它们。免疫学家正在定义一些分子机制，但仍有很多东西需要学习，特别是了解如何控制这些反应以避免过度炎症和组织损伤，同时将免疫系统引导到最有利于对抗感染因子的免疫反应类型。更好地了解这些问题将导致改进疫苗接种程序和更好地控制过度炎症条件的能力。

DESCRIPTION (provided by applicant): In recent years, Innate Immunity has gone from being the "immunologists' dirty little secret" to being among the most active and exciting areas of immunology. Many recognition molecules of vertebrate innate immune cells have been defined and much is now known about their mechanisms of action. Nonetheless, much remains to be learned before we truly understand how to harness these mechanisms for vaccination and cancer immunotherapy or how to block them to treat autoimmune and inflammatory disease. This proposed Program Project combines 4 investigators with established expertise in the area of innate immunity to pursue related studies developing out of their independent research efforts, but containing numerous connections and great potential for combined effort. In Project #1, Dr. DeFranco will utilize his newly created conditional allele of myd88 to dissect the cellular basis of Toll-like receptor signaling for systemic and mucosal immune responses, with emphasis on airways and fungal infections. In Project #2, Dr. Ma will analyze the role of the ubiquitin-modifying regulator A20 in dendritic cells for restraining TLR responses and preventing inflammatory disease. In Project #3, Dr. Lowell will determine the mechanism by which myeloid cells contribute to lupus-like autoimmunity in the Lyn-deficient mouse model. Finally, in Project #4, Dr. Locksley will determine how chitin, a polysaccharide found in fungi and invertebrates, promotes type 2 immunity and how it interacts with TLR signaling pathways to regulate the type of immune response. Lay Language: The immune system recognizes conserved elements of viruses, bacteria, fungi and multicellular invertebrates to allow it to detect infections and fight them. Immunologists are defining a number of the molecular mechanisms by which this is done, but much remains to be learned, particularly to understand how these reactions are controlled to avoid excessive inflammation and tissue injury, while directing the immune system toward the type of immune response most beneficial for fighting the infectious agent that is present. Better understanding of these issues will lead to improved vaccination procedures and better ability to control excessive inflammatory conditions.