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“免疫学家的肮脏小秘密”发展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，其作用机制也已了解很多。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，或者如何阻断它们来治疗自身免疫性和炎症性疾病之前，还有很多东西需要学习。本项目由4名在先天免疫领域具有成熟专业知识的研究人员组成，他们将在各自独立的研究基础上开展相关研究，但其中包含众多联系和巨大的合作潜力。在项目#1中，DeFranco博士将利用他新创建的myd88条件等位基因来解剖toll样受体信号传导系统和粘膜免疫反应的细胞基础，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剂A20在抑制TLR反应和预防炎症性疾病中的作用。在项目#3中，Lowell博士将确定骨髓细胞在淋巴细胞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，Locksley博士将确定几丁质（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。通俗语言：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。免疫学家正在定义一些分子机制，通过这些机制来实现这一点，但仍有很多东西有待了解，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，同时指导免疫系统朝着最有利于对抗现有感染因子的免疫反应类型发展。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. PROJECT 1: Cellular Basis of TLR signaling for Mucosal Immune Responses (DeFranco, A.) DESCRIPTION (provided by applicant): In recent years, Toll-like receptors (TLRs) have emerged as critical recognition elements of innate immunity, both for induction of inflammation at the site of an infection and for induction of an adaptive immune response. These receptors are expressed on the three major types of immune cells in many tissues, immature dendritic cells, tissue macrophages, and mast cells, as well as on several other types of cells. In the proposed project, we shall define which type of cell is responsible for mediating several TLR-based immune responses, systemically and in the airways. In these studies, we shall take advantage of a conditional allele we have engineered into the mouse germ line for the key TLR signaling adaptor molecule MyD88. This allows us to delete the gene encoding MyD88 specifically in particular cell types including dendritic cells, macrophages and neutrophils, B cells, and T cells. In Aim 1, we shall determine the role of dendritic cells in a mouse model of allergic asthma in which antigen + TLR ligands are introduced via the airways. In Aim 2, we shall analyze the immune response of mice to systemic or airway exposure to zymosan, a yeast cell wall preparation that is composed of chitin, ligands for TLR2 and ligands for C-type lectin receptors (dectin-1, etc.). We shall dissect the roles that these different innate immune ligands play in directing the nature of the immune response between Th1, Th2 and Th17. The contributions of particular cell types will also be determined. Finally, in Aim 3, we'll determine the cell type-specific roles of MyD88 in host defense to systemic infection by the fungal pathogen, Candida albicans. Lay Language Summary: The proposed studies will determine which immune cells in tissues are responsible for initiating immune responses to inhaled antigens as a model of allergic asthma, to infections with yeasts and molds. This will be accomplished by the use of genetically modified mice, in which key immune cell types are unable to recognize the presence of fungal cell walls. These studies will be useful for improving vaccination strategies and for developing novel strategies to block inflammation for patients with inflammatory diseases.