title: Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Lexmond
authors.forename: M
authors.initials: M
authors.lastname: Pardo
authors.forename: K
authors.initials: K
authors.lastname: Rooney
authors.forename: J A
authors.initials: JA
authors.lastname: Goettel
authors.forename: S B
authors.initials: SB
authors.lastname: Snapper
authors.forename: E H
authors.initials: EH
authors.lastname: Yen
authors.forename: E
authors.initials: E
authors.lastname: Dehlink
authors.forename: S
authors.initials: S
authors.lastname: Nurko
authors.forename: E
authors.initials: E
authors.lastname: Fiebiger
mesh_terms: D000293:Adolescent; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D057765:Eosinophilic Esophagitis / Q000175:diagnosis* / Q000235:genetics*; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D015415:Biomarkers; D016207:Cytokines; D053759:Interleukin-23; D012333:RNA, Messenger; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D000094632:Thymic Stromal Lymphopoietin
keywords: Th2 immune response; arachidonic acid metabolism; eosinophilic gastrointestinal diseases; leukotriene; reflux oesophagitis
references.citation: Clin Exp Allergy. 1995 May;25(5):467-79
references.pmid: 7553251
references.citation: Gastroenterology. 2009 Oct;137(4):1238-49
references.pmid: 19596009
references.citation: J Allergy Clin Immunol. 1988 Sep;82(3 Pt 1):414-8
references.pmid: 3170989
references.citation: J Allergy Clin Immunol. 2003 Oct;112(4):796-7
references.pmid: 14564365
references.citation: J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):506
references.pmid: 10452782
references.citation: J Allergy Clin Immunol. 2011 Jul;128(1):3-20.e6; quiz 21-2
references.pmid: 21477849
references.citation: Am J Gastroenterol. 2012 Oct;107(10):1503-11
references.pmid: 22777338
references.citation: Gut. 2010 Jan;59(1):12-20
references.pmid: 19528036
references.citation: Clin Exp Allergy. 2005 Nov;35(11):1421-2
references.pmid: 16297136
references.citation: Clin Gastroenterol Hepatol. 2012 Sep;10(9):988-96.e5
references.pmid: 22610003
references.citation: PLoS One. 2011 Apr 22;6(4):e19098
references.pmid: 21544204
references.citation: Immunol Allergy Clin North Am. 2009 Feb;29(1):197-211, xiii-xiv
references.pmid: 19141355
references.citation: J Clin Invest. 2001 Jan;107(1):83-90
references.pmid: 11134183
references.citation: Dis Esophagus. 2011 May;24(4):229-34
references.pmid: 21073625
references.citation: J Pediatr Gastroenterol Nutr. 2010 Nov;51(5):584-92
references.pmid: 20808250
references.citation: Clin Allergy. 1976 Jan;6(1):51-9
references.pmid: 1248098
references.citation: J Immunol. 2010 Nov 1;185(9):5040-7
references.pmid: 20870945
references.citation: Gut. 2003 Feb;52(2):181-5
references.pmid: 12524397
references.citation: Clin Exp Allergy. 2005 Nov;35(11):1423-31
references.pmid: 16297137
references.citation: J Allergy Clin Immunol. 2011 Jul;128(1):132-8
references.pmid: 21636117
references.citation: Ann Allergy Asthma Immunol. 2010 Jun;104(6):496-502
references.pmid: 20568382
references.citation: J Allergy Clin Immunol. 2003 Aug;112(2):252-62
references.pmid: 12897728
references.citation: N Engl J Med. 2004 Aug 26;351(9):940-1
references.pmid: 15329438
references.citation: Dig Dis Sci. 2011 Dec;56(12):3551-8
references.pmid: 21674173
references.citation: Clin Exp Allergy. 2003 Oct;33(10):1380-8
references.pmid: 14519144
references.citation: J Pediatr Gastroenterol Nutr. 2003 Feb;36(2):293-4
references.pmid: 12548071
references.citation: J Allergy Clin Immunol. 2007 Dec;120(6):1292-300
references.pmid: 18073124
references.citation: Nat Genet. 2010 Apr;42(4):289-91
references.pmid: 20208534
references.citation: Mucosal Immunol. 2011 Mar;4(2):139-47
references.pmid: 21228772
references.citation: N Engl J Med. 1999 Jan 21;340(3):197-206
references.pmid: 9895400
references.citation: J Allergy Clin Immunol. 2001 Dec;108(6):954-61
references.pmid: 11742273
references.citation: J Immunol Methods. 2011 Oct 28;373(1-2):192-9
references.pmid: 21903095
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4992-7
references.pmid: 22416124
references.citation: J Allergy Clin Immunol. 2011 Dec;128(6):1349-1350.e5
references.pmid: 22019091
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Ann Allergy Asthma Immunol. 2003 Jan;90(1):23-7
references.pmid: 12546333
references.citation: J Allergy Clin Immunol. 2010 Jul;126(1):140-9
references.pmid: 20538331
references.citation: Clin Rev Allergy Immunol. 1999 Spring-Summer;17(1-2):133-52
references.pmid: 10436863
references.citation: Pediatr Allergy Immunol. 2007 Sep;18(6):523-7
references.pmid: 17680911
references.citation: J Allergy Clin Immunol. 2011 Jan;127(1):208-17, 217.e1-7
references.pmid: 21211656
references.citation: Nat Biotechnol. 2008 Mar;26(3):317-25
references.pmid: 18278033
references.citation: J Clin Invest. 2006 Feb;116(2):536-47
references.pmid: 16453027
references.citation: Ann Allergy Asthma Immunol. 2007 Mar;98(3):207-14; quiz 214-7, 238
references.pmid: 17378251
references.citation: Immunol Allergy Clin North Am. 2007 Nov;27(4):651-64; vii
references.pmid: 17996582
references.citation: PLoS One. 2010 Aug 16;5(8):e12204
references.pmid: 20808937
references.citation: Biochem J. 2007 Aug 1;405(3):379-95
references.pmid: 17623009
references.citation: Am J Gastroenterol. 2006 May;101(5):1125-8
references.pmid: 16573772