Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis

Nat Med. 2013 Aug;19(8):1005-13. doi: 10.1038/nm.3281. Epub 2013 Jul 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Basophils / drug effects
  • Basophils / metabolism*
  • Cytokines / metabolism
  • Cytokines / pharmacology*
  • Disease Models, Animal
  • Eosinophilic Esophagitis / metabolism*
  • Eosinophilic Esophagitis / pathology*
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Eosinophils / ultrastructure
  • Esophagus / drug effects
  • Esophagus / pathology
  • Esophagus / ultrastructure
  • Female
  • Humans
  • Immunoglobulin E / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neutralization Tests

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Immunoglobulin E
  • thymic stromal lymphopoietin

Grant support