Key Allergic Mediators of Eosinophilic Esophagitis Identified

The hallmark of the allergic disease eosinophilic esophagitis (EoE), as its name indicates, is infiltration of the esophagus by eosinophils. Pathogenic effector T helper 2 (peT_H2) cells also accumulate in the esophagus and peripheral blood, producing interleukin (IL)-5 and IL-13, which promote inflammation.

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Wayne G. Shreffler, MD, PhD, chief of Pediatric Allergy & Immunology at MassGeneral Hospital for Children and investigator at the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, J. Christopher Love, PhD, of the Ragon Institute of Mass General, MIT and Harvard, and colleagues have identified signaling pathways that lead to recruitment of peT_H2cells to the esophagus in EoE. Their findings, which are expected to lead to better therapies for EoE, are published in Science Immunology.

Study Methods

The team analyzed cells from esophageal and duodenal biopsies of 10 patients with EoE (six with active disease, four in remission) and peripheral blood T-cells from eight of the patients. They also analyzed peripheral blood milk-reactive CD4+ T-cells from nine additional patients who had milk- or dairy-triggered EoE.

Key Results

Nuclear factor κB is an important mediator: Eosinophils from esophageal tissue exhibited upregulation of genes regulated by NF-κB. Activation of NF-κB in eosinophils was previously demonstrated to increase eosinophil survival and has been associated with IL-5 signaling, so cells with this gene signature are probably active mediators of inflammation in EoE.

GPR15 is a previously unidentified marker of esophagus homing: Expression of GPR15, a marker previously associated with homing to the colon and skin, was enriched on CD4+ cells in the esophagus and not the duodenum. GPR15 expression was also upregulated by peripheral peT_H2 clonotypes in the esophagus and on milk-reactive peT_H2 cells.

peT_H2 cells are a clonally expanded population associated with a distinct phenotypic state: Clonal expansion of peT_H2 cells, an important feature of an antigen-specific response, was detected in biopsy tissue and the periphery. In addition, there was evidence that multiple clonotypes can adopt a shared phenotype and be dominated by a small number of epitopes within an individual patient. These results support clinical observations that exposure to certain foods drives esophageal inflammation in EoE.

The pathogenicity of peT_H2 cells may result directly from their production of prostaglandin D2 (PGD2): A fundamental characteristic of peT_H2 cells across multiple allergic diseases is dysregulated lipid metabolism, which promotes the production of PGD2. In this study, peTH2 cells influenced tissue-resident eosinophils through the production of PGD2, a function also detected in peripheral peT_H2 cells and not conventional T_H2 cells.

Therapeutic Implications

Along with T_H2 cytokines, PGD2 may play a role in mediating the recruitment and activation of eosinophils in the esophagus during EoE. Studies that analyze the differentiation and behavior of peT_H2 cells could inform novel interventions for EoE and other allergic and eosinophilic diseases.

Furthermore, validation of allergen-specific peT_H2 cells in patients with EoE might identify specific allergen-derived epitopes. This would allow diagnosis of food triggers without burdening patients with trials of avoidance diets.

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