Role of basophils in initiating Th2 immune responses

描述(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免疫反应的机制在很大程度上仍不清楚。同样，针对多细胞寄生虫诱导保护性Th2反应的机制也不清楚。最近，我们以木瓜酶作为模型系统，证明嗜碱性粒细胞在变应原诱导的Th2反应中起着重要作用，它既是抗原提呈细胞，又是Th2极化细胞因子的来源。这项建议的目的是表征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，使其能够作为Th2反应的启动者。我们将研究嗜碱性粒细胞中由蛋白酶变应原激活的信号通路和转录因子。我们将检测变应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。我们将研究各种抗炎和免疫调节信号如何负向调节嗜碱性粒细胞的激活。最后，我们将研究嗜碱性粒细胞聚集到淋巴结以响应变应原攻击的机制。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作用提供重要的见解。 公共卫生相关性：尽管在了解诱导宿主防御感染的机制方面取得了巨大进展，但关于变应原如何触发致病性2型免疫反应几乎一无所知。我们最近发现，一种被称为嗜碱性粒细胞的特征不佳的细胞类型，在用变应原攻击后启动Th2免疫反应中发挥了关键作用。在这项应用中，我们建议研究蛋白酶变应原激活嗜碱性细胞的机制，并对嗜碱性细胞在启动Th2免疫反应中的作用提供新的见解。

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.