Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis
Background: Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. Objective: To gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. Methods: Bulk RNA-sequencing was performed on esophageal biopsies from adult EoE patients (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsies from non-EoE controls (n = 5) were also included. Results: At baseline, the transcriptome of the EoE patients showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its co-stimulatory effect on T cells, was the most dysregulated early EoE gene showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by stimulating differentiated esophageal epithelial cells with the key EoE cytokine interleukin-13. Conclusion: Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE, and suggests that TNFSF18 may be an important effector molecule in this response. Overall design: Bulk RNA-sequencing was performed on esophageal biopsies from adult EoE patients (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsies from non-EoE controls (n = 5) were also included.