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Key Allergic Mediators of Eosinophilic Esophagitis Identified

Key findings

  • This study was designed to understand the types and functions of cells present in tissue biopsies and peripheral blood of patients with eosinophilic esophagitis (EoE) and determine how these cells are altered in active disease versus remission
  • Key allergic mediators were present in the esophageal but not duodenal biopsies of patients with EoE, including tissue-resident eosinophils and pathogenic effector T helper 2 (peTH2) cells
  • Tissue-resident peTH2 cells were a clonally expanded population associated with a distinct phenotypic state involving prostaglandin D2 production
  • These cells were also enriched among food allergen–reactive CD4+ T-cells from the blood of patients with EoE and exhibited upregulation of GPR15, which likely promotes esophagus homing
  • Studies that analyze the differentiation and behavior of peTH2 cells could inform novel interventions for EoE, and validation of tissue homing allergen-specific peTH2 cells in the blood might permit diagnosis of food triggers without the need for trials of avoidance diets and invasive endoscopies

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 (peTH2) cells also accumulate in the esophagus and peripheral blood, producing interleukin (IL)-5 and IL-13, which promote inflammation.

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 peTH2cells 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 peTH2 clonotypes in the esophagus and on milk-reactive peTH2 cells.

peTH2 cells are a clonally expanded population associated with a distinct phenotypic state: Clonal expansion of peTH2 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 peTH2 cells may result directly from their production of prostaglandin D2 (PGD2): A fundamental characteristic of peTH2 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 peTH2 cells and not conventional TH2 cells.

Therapeutic Implications

Along with TH2 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 peTH2 cells could inform novel interventions for EoE and other allergic and eosinophilic diseases.

Furthermore, validation of allergen-specific peTH2 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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