Epithelial cells are uniquely positioned as the very first line of defense to recognize type-2 (Th2)-cell-mediated immune insults such as highly allergenic foods, proteolytic allergens and parasites. Herein, we focus on an endogenous pathway that normally curtails the development of Th2 immunity at the squamous mucosa mediated by the serine protease inhibitor SPINK7, whose loss of function is involved in unleashing marked Th2 related responses. We will focus on the prototypic human allergic disease, eosinophilic esophagitis (EoE), a chronic, food-driven, tissue-specific, esophageal, inflammatory allergic disease characterized by marked mucosal eosinophil accumulation and IBF mediated by loss of desmoglein (dsg)-1, not only because of the urgent need to uncover a better understanding of this emerging unmet disease, but also because it provides unique opportunities to examine mechanisms of tissue specificity and cross talk with other allergic diseases (e.g. atopic dermatitis [AD] and asthma), which are being studied throughout this Center Grant. Consistent with the theme of this Center Grant, EoE is a persistent disease of childhood that often progresses into fibrostenotic complications and likely other atopic diseases. This Project 2 of the Center Grant aligns with the central theme of uncovering mechanism for the induction of allergic disease and its persistence and interplay with the development of other allergic diseases.
We aim to test our central hypothesis is that decreased expression of SPINK7 in esophageal epithelium promotes EoE by unleashing a protease dependent pro-inflammatory response accompanied by IBF and TSLP production. This hypothesis will be tested in Aim 1, focused on determining the role of SPINK7 in regulating epithelial cell function;
Aim 2, focused on the role of SPINK7 regulation of the key pro-Th2 cytokine TSLP;
and Aim 3 focused on elucidating the transcriptional regulation and genetic contribution of SPINK7. Collectively, we aim to prove that SPINK7 has an essential role as a key innate checkpoint in the esophageal epithelium and its loss promotes EoE.
We have uncovered that there is marked loss of an anti-protease pathway in the tissue of allergic inflammation in the esophagus. We aim to prove that the decreased expression of this inhibitor (SPINK7) promotes allergic responses by unleashing a protease dependent pro-inflammatory response accompanied by loss of epithelial barrier function and production of pro-allergic mediators.
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