Modulation of Dectin-2 as a Therapeutic Approach to Dust Mite-Elicited Asthma

描述（由申请人提供）：屋尘螨是世界范围内支气管哮喘最常见的空气过敏原之一，50 - 85%的哮喘患者对屋尘螨过敏。屋尘螨（Dermatophagoides farinae, Df）提取物中富含甘露糖的聚糖可激活树突状细胞（DC）特异性c型凝集素受体Dectin-2，生成半胱氨酸白三烯、哮喘关键的促炎脂质介质和直接作用于T辅助17细胞的细胞因子。小鼠模型显示，Dectin-2对df引发的嗜酸性粒细胞和嗜中性粒细胞肺部炎症的发展至关重要。然而，Df中相关胶聚糖的结构以及Dectin-2如何识别配体尚不清楚。我们假设Dectin-2是哮喘中启动和促进对主要家庭过敏原免疫反应的关键传感分子。特异性目的1是确定Dectin-2中识别屋尘螨过敏原中富甘露糖聚糖配体的关键氨基酸残基。了解Dectin-2的配体结合模式有助于开发特异性抑制剂，尽管Dectin-2抑制可能不利于宿主防御真菌。特异性目的2是研究在小鼠模型中，工程Dectin-2碳水化合物识别结构域是否可以竞争改善屋尘螨诱导的过敏性肺部炎症。利用工程Dectin-2碳水化合物识别结构域作为捕获DC激活的过敏原相关配体的工具可能更适合新的治疗方法。

DESCRIPTION (provided by applicant): House dust mites are one of the commonest aeroallergens for bronchial asthma worldwide, and 50 - 85% of asthmatics are typically allergic to house dust mites. Mannose-rich glycans in extracts of the house dust mite, Dermatophagoides farinae (Df), activate the dendritic cell (DC)-specific C-type lectin receptor, Dectin-2, to generate cysteinyl leukotrienes, critical proinflammatory lipid mediators for asthma, and cytokines directed to T helper 17 cells. Mouse models show that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation. However, the structure of the responsible gylcans in Df and how Dectin-2 recognizes the ligands are unknown. We hypothesize that Dectin-2 is the critical sensing molecule for the initiation and promotion of immune responses to major household allergens in asthma. Specific Aim1 is to determine the critical amino acid residues in Dectin-2 for recognizing mannose-rich glycan ligands in house dust mite allergen. Understanding of the ligand-binding mode of Dectin-2 should help the development of specific inhibitors although Dectin-2 inhibition may not be beneficial for host defense against fungi. Specific Aim2 is to examine whether an engineered Dectin-2 carbohydrate-recognition domain(s) can compete to ameliorate house dust mite-induced allergic pulmonary inflammation in mouse models. Utilizing an engineered Dectin-2 carbohydrate-recognition domain(s) as a tool for capturing allergen-associated ligands for DC activation may be better for new therapy.