Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients

Clin Exp Allergy. 2013 Aug;43(8):902-13. doi: 10.1111/cea.12146.

Abstract

Background: Cysteinyl leukotrienes contribute to Th2-type inflammatory immune responses. Their levels in oesophageal tissue, however, do not distinguish patients with eosinophilic oesophagitis (EoE) from controls.

Objective: We asked whether mRNA levels of leukotriene C4 synthase (LTC4 S), a key regulator of leukotriene production, could serve as a marker for EoE.

Methods: Digital mRNA expression profiling (nCounter(®) Technology) was performed on proximal and distal oesophageal biopsies of 30 paediatric EoE patients and 40 non-EoE controls. Expression data were confirmed with RT-qPCR. LTC4 S mRNA levels were quantified in whole blood samples. Leukotriene E4 was measured in urine.

Results: LTC4 S mRNA levels were elevated in proximal (2.6-fold, P < 0.001) and distal (2.9-fold, P < 0.001) oesophageal biopsies from EoE patients. Importantly, increased LTC4 S mRNA transcripts identified a subpopulation of EoE patients (28%). This patient subgroup had higher serum IgE levels (669 U/mL vs. 106 U/mL, P = 0.01), higher mRNA transcript numbers of thymic stromal lymphopoietin (TSLP) (1.6-fold, P = 0.009) and CD4 (1.4-fold, P = 0.04) but lower IL-23 mRNA levels (0.5-fold, P = 0.04). In contrast, elevated levels of IL-23 mRNA were found in oesophageal biopsies of patients with reflux oesophagitis. LTC4 S mRNA transcripts in whole blood and urinary excretion of leukotriene E4 were similar in EoE patient subgroups and non-EoE patients.

Conclusion & clinical relevance: Elevated oesophageal expression of LTC4 S mRNA is found in a subgroup of EoE patients, concomitant with higher serum IgE levels and an oesophageal transcriptome indicative of a more-pronounced allergic phenotype. Together with TSLP and IL-23 mRNA levels, oesophageal LTC4 S mRNA may facilitate diagnosis of an EoE subpopulation for personalized therapy.

Keywords: Th2 immune response; arachidonic acid metabolism; eosinophilic gastrointestinal diseases; leukotriene; reflux oesophagitis.

Publication types

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

MeSH terms

  • Adolescent
  • Biomarkers
  • Child
  • Child, Preschool
  • Cytokines / genetics
  • Cytokines / metabolism
  • Eosinophilic Esophagitis / diagnosis*
  • Eosinophilic Esophagitis / genetics*
  • Eosinophils / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression*
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / metabolism
  • Humans
  • Infant
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism
  • Male
  • Mast Cells / metabolism
  • RNA, Messenger / genetics
  • Sensitivity and Specificity
  • Thymic Stromal Lymphopoietin

Substances

  • Biomarkers
  • Cytokines
  • Interleukin-23
  • RNA, Messenger
  • Glutathione Transferase
  • leukotriene-C4 synthase
  • Thymic Stromal Lymphopoietin