Role of basophils 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免疫反应的机制在很大程度上仍然未知。同样，诱导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细胞在过敏原诱导的Th2反应中发挥重要作用，作为抗原呈递细胞和Th2极化细胞因子的来源。本提案的目的是表征蛋白酶过敏原的作用机制，并阐明嗜碱性细胞的关键特征，使其能够作为Th2反应的启动者。我们将研究蛋白酶过敏原在嗜碱性细胞中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。我们将研究各种抗炎和免疫调节信号如何负调控嗜碱性粒细胞的激活。最后，我们将探讨嗜碱性粒细胞在应对过敏原挑战时向淋巴结募集的机制。这些研究应该为了解非常重要但尚不清楚的致敏性机制和嗜碱性细胞在过敏反应中的功能提供重要的见解。

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.