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 .
|Sivaprasad, Umasundari; Kinker, Kayla G; Ericksen, Mark B et al. (2015) SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis. J Invest Dermatol 135:160-9|
|Ji, Hong; Zhang, Xue; Oh, Sunghee et al. (2015) Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells. J Allergy Clin Immunol 135:236-44|
|Wen, Ting; Dellon, Evan S; Moawad, Fouad J et al. (2015) Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol 135:187-97|
|Sherrill, Joseph D; Rothenberg, Marc E (2014) Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin North Am 43:269-80|
|Biagini Myers, Jocelyn M; Martin, Lisa J; Kovacic, Melinda Butsch et al. (2014) Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma. J Allergy Clin Immunol 134:891-899.e3|
|Sherrill, J D; Kiran, K C; Blanchard, C et al. (2014) Analysis and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes Immun 15:361-9|
|Zhang, Zhonghua; Xiao, Chang; Gibson, Aaron M et al. (2014) EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. J Immunol 192:859-66|
|Krishnamurthy, Purna; Sherrill, Joseph D; Parashette, Kalyan et al. (2014) Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis. J Allergy Clin Immunol 133:577-80|
|Jung, YunJae; Rothenberg, Marc E (2014) Roles and regulation of gastrointestinal eosinophils in immunity and disease. J Immunol 193:999-1005|
|Sherrill, J D; Kc, K; Wu, D et al. (2014) Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol 7:718-29|
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