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.

Public Health Relevance

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.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Davidson, Wendy F
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Brigham and Women's Hospital
United States
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Lee, Min Jung; Yoshimoto, Eri; Saijo, Shinobu et al. (2016) Phosphoinositide 3-Kinase δ 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