Innate immune regulation of inflammation and adaptive immunity

描述(申请人提供)：近年来，天然免疫已经从“免疫学家肮脏的小秘密”变成了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经被定义，并且现在对它们的作用机制有了更多的了解。然而，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，或者如何阻止它们治疗自身免疫性和炎症性疾病之前，还有很多事情要做。这一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，以进行来自他们独立研究努力的相关研究，但包含许多联系和共同努力的巨大潜力。在项目1中，德弗兰科博士将利用他新创造的条件等位基因MyD88来剖析Toll样受体信号在全身和粘膜免疫反应中的细胞基础，重点是呼吸道和真菌感染。在项目2中，马博士将分析树突状细胞中泛素修饰调节因子A20在抑制TLR反应和预防炎症性疾病中的作用。在项目3中，洛厄尔博士将确定髓系细胞在LYN缺陷小鼠模型中促进狼疮样自身免疫的机制。最后，在项目#4中，洛克斯利博士将确定几丁质--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，调节免疫反应的类型。外行语言：免疫系统识别病毒、细菌、真菌和多细胞无脊椎动物的保守成分，使其能够检测感染并与之抗争。免疫学家正在确定完成这一任务的一些分子机制，但仍有许多需要了解，特别是要了解如何控制这些反应，以避免过度炎症和组织损伤，同时引导免疫系统做出最有利于对抗现有感染性病原体的免疫反应类型。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.