Invariant natural killer T cells in children with eosinophilic esophagitis

Clin Exp Allergy. 2014 Jan;44(1):58-68. doi: 10.1111/cea.12201.

Abstract

Background: Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in which dietary antigens (in particular, milk) play a major role. EoE is most likely a mixed IgE and non-IgE food-mediated reaction in which overexpression of Th2 cytokines, particularly IL-13, play a major role; however, the cells responsible for IL-13 overexpression remain elusive. Th2-cytokines are secreted following the ligation of invariant natural killer T cell receptors to sphingolipids (SLs). Sphingolipids (SLs) are presented via the CD1d molecule on the INKTs surface. Cow's milk-derived SL has been shown to activate iNKTs from children with IgE-mediated food allergies to milk (FA-MA) to produce Th2 cytokines. The role of iNKTs and milk-SL in EoE pathogenesis is currently unknown.

Objective: The aim of this study was to investigate the role of iNKTs and milk-SL in EoE.

Methods: Peripheral blood mononuclear cells (PBMCs) from 10 children with active EoE (EoE-A), 10 children with controlled EoE (EoE-C) and 16 healthy controls (non-EoE) were measured ex vivo and then incubated with α-galactosylceramide (αGal) and milk-SL. INKTs from peripheral blood (PB) and oesophageal biopsies were studied.

Results: EoE-A children had significantly fewer peripheral blood iNKTs with a greater Th2-response to αGal and milk-SM compared with iNKTs of EoE-C and non-EoE children. Additionally, EoE-A children had increased iNKT levels in oesophageal biopsies compared with EoE-C children.

Conclusion: Milk-SLs are able to activate peripheral blood iNKTs in EoE-A children to produce Th2 cytokines. Additionally, iNKT levels are higher at the site of active oesophageal eosinophilic inflammation.

Clinical relevance: This study suggests that sphingolipids (SLs) contained in milk may drive the development of EoE by promoting an iNKT-cell-mediated Th2-type cytokine response that facilitates eosinophil-mediated allergic inflammation.

Keywords: Eosinophilic esophagitis; invariant natural killer T cells; sphingolipids.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Allergens / immunology
  • Animals
  • Child
  • Child, Preschool
  • Cytokines / biosynthesis
  • Eosinophilic Esophagitis / drug therapy
  • Eosinophilic Esophagitis / immunology*
  • Eosinophilic Esophagitis / metabolism
  • Female
  • Humans
  • Immunophenotyping
  • Lymphocyte Count
  • Male
  • Milk / immunology
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Phenotype
  • Receptors, CCR3 / metabolism
  • Receptors, CCR4 / metabolism
  • Receptors, CCR5 / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism

Substances

  • Allergens
  • Cytokines
  • Receptors, CCR3
  • Receptors, CCR4
  • Receptors, CCR5