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

• 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
• 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

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）：过敏性疾病是人类健康和福祉的主要负担。然而，过敏原诱导致病性 Th2 免疫反应的机制仍然很大程度上未知。同样，诱导针对多细胞寄生虫的保护性 Th2 反应的机制也不清楚。使用蛋白酶过敏原木瓜蛋白酶作为模型系统，我们最近证明嗜碱性粒细胞通过充当抗原呈递细胞和 Th2 极化细胞因子的来源，在过敏原诱导的 Th2 反应中发挥重要作用。该提案的目的是描述蛋白酶过敏原的作用机制，并阐明嗜碱性粒细胞的关键特征，使其能够发挥 Th2 反应引发剂的功能。我们将研究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。我们将研究嗜碱性粒细胞活化如何受到各种抗炎和免疫调节信号的负调节。最后，我们将研究嗜碱性粒细胞招募至淋巴结以应对过敏原挑战的机制。这些研究应该为非常重要但知之甚少的过敏性机制和嗜碱性粒细胞在过敏反应中的功能提供重要的见解。 公共卫生相关性：尽管在理解诱导宿主防御感染的机制方面取得了巨大进展，但对于过敏原如何触发致病性 2 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特征较差的细胞类型在过敏原攻击后启动 Th2 免疫反应中发挥着关键作用。在本申请中，我们打算研究蛋白酶过敏原激活嗜碱性粒细胞的机制，并为嗜碱性粒细胞在启动 Th2 免疫反应中的功能提供新的见解。