Mechanisms Regulating Allergic Sensitization to Cockroach Allergen
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Allergic asthma is an inflammatory disease of the airways driven by an overactive immune response against allergens. Allergen-specific TH2 cells are critical to the pathogenesis of asthma but factors controlling the initiation of TH2 responses are not well understood. The emerging picture is one that pinpoints a role for airway epithelial cells and epithelial-derived cytokines in promoting TH2 immunity to allergens. However, allergens are structurally diverse and can elicit different epithelial-derived cytokines. Thus, there are multiple pathways that lead to TH2 immunity and mechanisms of sensitization that are unique to individual allergens remain to be elucidated. Cockroach allergen (CRA) is an environmental allergen that is strongly associated with the incidence of allergic asthma. Despite its clinical importance, very little is known about the molecular and cellular pathways involved in allergic sensitization to CRA. To determine the mechanisms that regulate allergic sensitization to CRA, we intranasally sensitized and challenged mice with CRA to induce allergic airway inflammation with hallmark features of asthma. Using this model, we demonstrate that allergic sensitization to CRA requires activation of airway epithelial cells. MyD88 deletion in airway epithelial cells reduced allergic airway response to CRA as well as production of GM-CSF during sensitization. Using a neutralizing antibody against GM-CSF, we showed that GM-CSF is essential for TH2 priming and allergic sensitization to CRA, likely through activation of dendritic cells. When GM-CSF was intranasally delivered during sensitization, TH2-mediated eosinophilia was restored in the absence of MyD88. Thus, airway epithelial cells promote allergic sensitization to CRA through production of GM-CSF.