IL-17 Receptor Signaling in the Oral Mucosa

描述(申请人提供)：口腔是许多传染性病原体的入口。然而，尽管在黏膜免疫领域取得了进展，但令人惊讶的是，人们对口腔粘膜的免疫机制知之甚少。虽然我们对粘膜免疫的大部分了解都来自于对胃肠道的研究，但其他粘膜部位的免疫并不总是与肠道平行。这种二分法的一个很好的例子是对白色念珠菌的研究，白色念珠菌是一种共生的二态真菌，在口腔、食道和阴道粘膜表面定居。在健康的个体中，白色念珠菌的定植是非致病性的。然而，在免疫缺陷的情况下，如艾滋病毒/艾滋病、干燥综合征或先天性免疫缺陷，这种微生物会引起严重的口腔机会性感染，称为“鹅口疮”或口咽部念珠菌病(OPC)。OPC在HIV/AIDS中的高发病率(&gt；90%)表明CD4+T细胞参与了对白色念珠菌的免疫。直到最近，这还被认为是Th1细胞及其标志性细胞因子IFNG的专属领域。2005年，一种新的T细胞亚群被发现，它能产生IL-17，因此被称为“Th17”。产生IL-17的细胞高度集中在粘膜表面，特别是胃肠道，并在艾滋病时选择性地被耗尽。在粘膜念珠菌病的胃肠道模型中，Th1细胞和IFNG似乎对宿主具有保护作用，而IL-17和Th17诱导的细胞因子IL-23促进了有害的免疫病理。相反，我们小组在小鼠身上的工作和对IL-17R缺乏的人类的新研究表明，IL-17是对抗口腔粘膜念珠菌病的免疫的重要介质。然而，IL-17驱动宿主抵抗念珠菌的具体机制尚不清楚，包括口腔粘膜内的靶细胞或IL-17受体介导的下游受体信号转导机制。这项应用的目的是通过特别关注IL-1及其受体在介导口腔内对白色念珠菌的免疫防御中的作用来填补我们知识的这一空白。为此，我们将使用一系列基因靶向的小鼠来系统地定义OPC背景下重要的IL-17反应细胞类型，并描绘IL-17受体介导宿主防御所使用的特定分子信号通路。 公共卫生相关性：口腔念珠菌病，也称为口腔鹅口疮，是一种定义为艾滋病的口腔粘膜真菌感染。这种疾病还会困扰接受化疗的个人、服用免疫抑制药物的移植患者、使用吸入性皮质类固醇药物的哮喘患者或其他免疫功能受损的人，如婴儿和老年人。该项目的目标是详细了解免疫系统如何正常控制口腔念珠菌病，重点是一种特定的细胞因子受体IL-17R的作用。这项研究的长期目标是为口腔粘膜疾病开发更好的治疗方法或疫苗，并了解抑制特定免疫事件的治疗方法的后果。

DESCRIPTION (provided by applicant): The oral cavity is a portal of entry for many infectious pathogens. However, despite advances in the field of mucosal immunity, mechanisms of immunity in the oral mucosa are surprisingly poorly understood. Whereas much of our understanding of mucosal immunity comes from studies of the gastrointestinal tract, immunity at other mucosal sites does not always parallel the gut. A good example of this dichotomy comes from studies of Candida albicans, a commensal dimorphic fungus that colonizes oral, esophageal and vaginal mucosal surfaces. In healthy individuals, C. albicans colonization is non-pathogenic. However, in conditions of immunodeficiency such as HIV/AIDS, Sj¿gren's syndrome or congenital immunodeficiency, this microbe causes severe opportunistic infections of the oral cavity, known as "thrush" or oropharyngeal candidiasis (OPC). The high incidence of OPC in HIV/AIDS (>90%) implicates CD4+ T cells in immunity against C. albicans. Until recently, this was thought to be the province of Th1 cells and their signature cytokine, IFNg. In 2005, a new subset of T cell was discovered that produces IL-17, and hence is known as "Th17." IL-17-producing cells are highly enriched at mucosal surfaces, particularly the GI tract, and are selectively depleted in AIDS. In a gastrointestinal model of mucosal candidiasis, Th1 cells and IFNg appear to be host-protective, whereas IL-17 and the Th17-inductive cytokine IL-23 promote a deleterious immunopathology. In contrast, work from our group in mice and new studies in IL-17R-deficient humans indicate that IL-17 is an essential mediator of immunity against oral mucosal candidiasis. However, the specific mechanisms by which IL-17 drives host defense against Candida is not known, including the target cells within the oral mucosa or the downstream receptor signaling mechanisms mediated by the IL-17 receptor. The objective of this application is to fill this gap in our knowledge, by focusing specifically on the role of IL-1 and its receptor in mediating immune defense against Candida albicans in the oral cavity. To that end, we will use a series of gene-targeted mice to systematically define the important IL-17-responsive cell types in the context of OPC, and to delineate specific molecular signaling pathways used by the IL-17 receptor to mediate host defense. PUBLIC HEALTH RELEVANCE: Oral candidiasis, also known as oral thrush, is an AIDS-defining fungal infection of the oral mucosa. This disease also afflicts individuals on chemotherapy, transplant patients taking immunosuppressive drugs, asthma patients using inhaled corticosteroid drugs or others with compromised immune function such as infants and the elderly. The objective of this project is to understand in detail how the immune system normally keeps oral candidiasis under control, with an emphasis on the role of a particular cytokine receptor, the IL-17R. The long-term goal of this research is to develop better therapies or vaccines for mucosal disease of the oral cavity, and to understand the consequences of therapies that suppress specific immune events.