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Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.

ABSTRACT: Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

SUBMITTER: Noti M

PROVIDER: S-EPMC3951204 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.

Noti Mario M Wojno Elia D Tait ED Kim Brian S BS Siracusa Mark C MC Giacomin Paul R PR Nair Meera G MG Benitez Alain J AJ Ruymann Kathryn R KR Muir Amanda B AB Hill David A DA Chikwava Kudakwashe R KR Moghaddam Amin E AE Sattentau Quentin J QJ Alex Aneesh A Zhou Chao C Yearley Jennifer H JH Menard-Katcher Paul P Kubo Masato M Obata-Ninomiya Kazushige K Karasuyama Hajime H Comeau Michael R MR Brown-Whitehorn Terri T de Waal Malefyt Rene R Sleiman Patrick M PM Hakonarson Hakon H Cianferoni Antonella A Falk Gary W GW Wang Mei-Lun ML Spergel Jonathan M JM Artis David D

Nature medicine 20130721 8

Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis ha ...[more]

PMID: 23872715

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Project description:Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression.

Dataset Information

Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.

Publications

Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.

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