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.
This project will determine the mechanism by which a C-type lectin receptor called Dectin-2 recognizes house dust mite allergen, a critical process of the initiation of asthma, by using mouse models and molecular biological approaches. Findings should provide new therapeutic strategy to asthma and other allergic diseases.
|Lee, Min Jung; Yoshimoto, Eri; Saijo, Shinobu et al. (2016) Phosphoinositide 3-Kinase Î´ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol 197:278-87|
|Kanaoka, Yoshihide; Boyce, Joshua A (2014) Cysteinyl leukotrienes and their receptors; emerging concepts. Allergy Asthma Immunol Res 6:288-95|
|Parsons, Matthew W; Li, Li; Wallace, Aaron M et al. (2014) Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol 192:1361-71|