Molecular mechanisms of allergic type 2 immunity in the pathogenesis of Crohn's disease: From epithelial alarmins to IgE signaling.

Crohn's disease (CD) is a chronic inflammatory bowel disorder driven by complex interactions between genetic susceptibility, gut microbiota, and immune dysregulation, typically associated with Th1 and Th17 responses. However, emerging evidence highlights that type 2 allergic mechanisms also significantly contribute to CD pathogenesis. This review examines the cellular and molecular basis of allergic pathways in CD, focusing on IgE-mediated hypersensitivity, mast cell and eosinophil effector functions, and Th2 cytokines (IL-4, IL-5, IL-13). Key epithelial-derived alarmins-namely IL-33, TSLP, and IL-25-are discussed as critical upstream mediators linking mucosal barrier injury to type 2 immune activation in the CD gut. Elevated serum IgE, intestinal mast cell infiltration, and tissue eosinophilia have consistently been documented in CD patients. Mechanistically, FcεRI signaling on mast cells triggers degranulation and release of histamine, proteases, and pro-inflammatory cytokines such as TNF-α and IL-6, leading to increased epithelial permeability and visceral hypersensitivity. Moreover, crosstalk between Th2 and Th1/Th17 pathways further amplifies chronic intestinal inflammation. Understanding these allergic mechanisms opens novel therapeutic avenues, including anti-IgE (omalizumab), anti-IL-4/IL-13 (dupilumab), anti-IL-33 (itepekimab), anti-TSLP (tezepelumab), and mast cell stabilizers (ketotifen). This review integrates current molecular evidence on allergic reactions in CD and highlights their clinical and therapeutic relevance. Recognizing type 2 immune signatures in subsets of CD patients may enable more personalized treatment strategies.