Role of basophils in initiating Th2 immune responses

嗜碱性粒细胞在启动 Th2 免疫反应中的作用

基本信息

批准号：
8066599
负责人：
Ruslan Medzhitov
金额：
$ 40.91万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066599
关键词：
Allergens Allergic Allergic Disease Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen-Presenting Cells Antigens Asthma Bacteria Basophils Biological Models Cell Adhesion Molecules Cysteine Protease Dendritic Cells Development Goals Health Helminths Host Defense Human Hypersensitivity Immune response Immune system Immunization In Vitro Infection Interleukin-12 Interleukin-3 Interleukin-4 Interleukin-6 Knowledge Life Cycle Stages Papain Parasites Pathway interactions Pattern recognition receptor Peptide Hydrolases Personal Satisfaction Phenotype Plants Play Production Proteins Receptor Cell Regulation Role Signal Pathway Signal Transduction Signaling Molecule Source Therapeutic Intervention Virus activating transcription factor allergic response cell type chemokine chemokine receptor clinically relevant cytokine fungus in vivo insight lymph nodes occupational hazard prophylactic public health relevance receptor response sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Allergic diseases represent a major burden to human health and well-being. However, the mechanisms whereby allergens induce the pathogenic Th2 immune responses remain largely unknown. Similarly, the mechanisms of induction of protective Th2 responses against multi-cellular parasites are poorly defined. Using a protease allergen papain as a model system, we have recently demonstrated that basophils play an essential role in allergen-induced Th2 responses, by functioning as antigen-presenting cells and as a source of Th2 polarizing cytokines. The goal of this proposal is to characterize the mechanism of action of protease allergens and to elucidate key features of basophils that enable their function as initiators of Th2 responses. We will investigate signaling pathways and transcription factors activated by protease allergens in basophils. We will examine the phenotype of allergen-activated basophils and compare it to the FceRI and IL-3 receptor activated basophils. We will examine how basophil activation is negatively regulated by a variety of anti-inflammatory and immunoregulatory signals. Finally, we will investigate the mechanisms of basophil recruitment to the lymph nodes in response to allergen challenge. These studies should provide important insights into very important but poorly understood mechanisms of allergenicity and the function of basophils in allergic responses. PUBLIC HEALTH RELEVANCE: Despite the tremendous progress in understanding the mechanisms of induction of host defense from infection, there is almost nothing known about how allergens trigger the pathogenic type2 immune responses. We recently found that a poorly characterize cell type called basophil, play a key role in initiating Th2 immune responses following challenge with an allergen. In this application we propose to investigate the mechanism of basophil activation by protease allergens and to provide new insights into basophil function in initiating Th2 immune responses.

描述（由申请人提供）：过敏疾病代表了人类健康和福祉的重大负担。但是，过敏原诱导致病性Th2免疫反应的机制在很大程度上未知。同样，针对多细胞寄生虫的保护性TH2反应的诱导机制的定义很差。我们使用蛋白酶过敏蛋白酶作为模型系统，最近证明了嗜碱性粒细胞在过敏原诱导的Th2反应中起着至关重要的作用，通过充当抗原呈递细胞以及Th2偏振细胞因子的来源。该提案的目的是表征蛋白酶过敏原作用机理，并阐明嗜碱性粒细胞的关键特征，以使其作为TH2反应的发起人的功能。我们将研究由嗜碱性粒细胞中蛋白酶过敏原激活的信号通路和转录因子。我们将检查过敏原激活的嗜碱性粒细胞的表型，并将其与FCERI和IL-3受体激活的嗜碱性粒细胞进行比较。我们将研究嗜碱性激活如何受到各种抗炎和免疫调节信号的负调节。最后，我们将根据过敏原挑战研究嗜碱性粒细胞募集到淋巴结的机制。这些研究应提供有关非常重要但知之甚少的过敏性机制以及嗜碱性粒细胞在过敏反应中的功能的重要见解。公共卫生相关性：尽管在理解宿主防御感染的诱导机制方面取得了巨大进展，但对过敏原如何触发致病型免疫反应几乎一无所知。我们最近发现，一种称为嗜碱性粒细胞的细胞类型的特征很差，在对过敏原挑战后启动Th2免疫反应中起着关键作用。在此应用中，我们建议研究蛋白酶过敏原激活嗜碱性粒细胞的机制，并在启动Th2免疫反应时对嗜碱性粒细胞功能提供新的见解。