Allergic diseases continue to pose a significant public health burden in modernized societies. Although the etiology of allergic diseases is unknown, they are thought to develop as a result of aberrant Th2 immune responses in genetically susceptible individuals. Despite this recognition, the factors driving Th2-mediated immune responses have remained elusive. Our preliminary data suggests the novel paradigm that allergen exposure induces epithelial cell injury which results in the release of an epithelial-derived factor, trefoil factor 2. Tff2, in turn induces the release of the """"""""alarmin"""""""" IL-33, which drives Th2 cytokine production in innate immune cells. The production of Th2 cytokines, amplifies and perpetuates the response by driving additional Tff2 release. Importantly, we show that TFF2 levels are elevated in epithelial cells from asthmatic children undergoing an acute attack as compared to cells from healthy controls. Thus the goal of this proposal is to test the novel hypothesis that aberrant epithelial cell production of TFF2 is important in the induction and expression of Th2-mediated allergic responses in an IL-33-dependent manner. Moreover, we propose that genetic variation in the genes controlling this pathway (TFF2, IL-33, IL-1RL1) enhances the risk of developing allergic diseases (allergic asthma, atopic dermatitis, allergic rhinitis, eosinophilic esphagitis) in children. To test this hypothesis, we propose the following specific aims: 1) To determine the contribution of the Tff2/IL-33 pathway to the initiation of Th2-mediated allergic airway responses;2) To determine the mechanism by which TFF2 mediates IL-13-dependent AHR and mucus cell metaplasia;and 3) To determine whether dysregulation of the TFF2/IL-33 pathway contributes to the risk of developing allergic disorders in cohorts of children recruited from the Cincinnati Area. The studies in this Project are closely aligned with and benefit from the resources and information generated in Projects 1 and 2 of this U19, which are also focused on defining the contribution of altered mucosal epithelial function in the etiology of allergic diseases. Identification of the Tff2/IL-33 pathway as an important driver and amplifier of the allergic response should lead to the development of disease modifying therapies for the treatment of allergic disorders.
Although allergic diseases have long posed a significant public health burden, the factors predisposing some individuals to the development of these disorders are unknown. Herein, we will test the novel hypothesis that dysregulation of the production of an epithelial-derived factor. Trefoil factor 2, drives susceptibility to allergic disorders through a pathway involving the alarmin, IL-33. These studies will greatly inform the development nf novel treatment mnrJalitifis fr^r these dfihilitatino disorders .
|Davis, Benjamin P; Stucke, Emily M; Khorki, M Eyad et al. (2016) Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 1:e86355|
|Zhang, Zhonghua; Biagini Myers, Jocelyn M; Brandt, Eric B et al. (2016) Î²-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses. J Allergy Clin Immunol :|
|Ji, Hong; Biagini Myers, Jocelyn M; Brandt, Eric B et al. (2016) Air pollution, epigenetics, and asthma. Allergy Asthma Clin Immunol 12:51|
|Gupta, Jayanta; Johansson, Elisabet; Bernstein, Jonathan A et al. (2016) Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry. J Allergy Clin Immunol 138:676-99|
|Davis, Benjamin P; Rothenberg, Marc E (2016) Mechanisms of Disease of Eosinophilic Esophagitis. Annu Rev Pathol 11:365-93|
|Molina-Infante, Javier; Bredenoord, Albert J; Cheng, Edaire et al. (2016) Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 65:524-31|
|Ulm, Ashley; Mayhew, Christopher N; Debley, Jason et al. (2016) Cultivate Primary Nasal Epithelial Cells from Children and Reprogram into Induced Pluripotent Stem Cells. J Vis Exp :|
|Davis, Benjamin P; Epstein, Tolly; Kottyan, Leah et al. (2016) Association of eosinophilic esophagitis and hypertrophic cardiomyopathy. J Allergy Clin Immunol 137:934-936.e5|
|Giridhar, Premkumar Vummidi; Bell, Sheila M; Sridharan, Anusha et al. (2016) Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens. J Immunol 197:4228-4239|
|D'Mello, R J; Caldwell, J M; Azouz, N P et al. (2016) LRRC31 is induced by IL-13 and regulates kallikrein expression and barrier function in the esophageal epithelium. Mucosal Immunol 9:744-56|
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