title: Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios.
abstract: BACKGROUND
  Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T regulatory cells (Treg) are critical for intestinal immune homoeostasis.
  
  
  OBJECTIVE
  To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC.
  
  
  METHODS
  Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls.
  
  
  RESULTS
  The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis.
  
  
  CONCLUSIONS
  The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, 2215 B Garland Ave., 1125 MRB IV/Light Hall, Nashville, TN 37232-0656, USA. hendrik.weitkamp@vanderbilt.edu
authors.forename: Jörn-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koyama
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rock
authors.forename: Hernan
authors.initials: H
authors.lastname: Correa
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.forename: Pranathi
authors.initials: P
authors.lastname: Matta
authors.forename: Kyra
authors.initials: K
authors.lastname: Oswald-Richter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: Brian G
authors.initials: BG
authors.lastname: Engelhardt
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D020345:Enterocolitis, Necrotizing / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors