IFNγ Signaling Impairs Regulatory B Cell Function Resulting in Worse Control of Esophageal Food Allergy.

BACKGROUND: Eosinophilic Esophagitis (EoE) is a chronic food allergy that causes esophageal inflammation and fibrosis and manifests with symptoms of reflux, chest pain, swallowing difficulty, and food impactions. Though the prevalence of EoE is increasing by ~15% each year, our understanding of EoE immunopathology is limited. A noted feature of EoE is the presence of food-specific IgG4 antibodies in the circulation and esophageal tissue. Production of IgG4 is confined to IL-10+ B cells (Bregs) in other allergic diseases, suggesting Bregs may be present in EoE.

METHODS: We examined circulating Bregs in patients with EoE milk allergy. In parallel, we performed mechanistic investigations of the role of Bregs in a murine model of food-antigen-dependent EoE. Flow cytometry and histologic analyses were used to assess esophageal and draining lymph node immune cells, and in vitro assays were used to evaluate Breg functional capacity.

RESULTS: Breg frequency was reduced in both EoE milk allergic subjects and an EoE disease model. Murine Breg suppressive capacity was impaired during EoE-like inflammation. Inducible deletion of Breg-derived IL-10 worsened EoE-like inflammation, while adoptive transfer of IL-10 sufficient Bregs suppressed DC activation and improved esophageal eosinophilia. IFNγ was sufficient to suppress Breg expansion and IL-10 production in vitro and contributed to Breg dysfunction and esophageal inflammation in vivo.

CONCLUSION: Bregs play an immunoregulatory role during EoE by controlling esophageal eosinophilia but are functionally impaired due to IFNγ-mediated signaling. These findings have important implications for understanding EoE's etiology and implementing future therapies that target IFNγ.