Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios

• Published in: Gut Vol. 62; no. 1; pp. 73 - 82
• Main Authors: Weitkamp, Jörn-Hendrik, Koyama, Tatsuki, Rock, Michael T, Correa, Hernan, Goettel, Jeremy A, Matta, Pranathi, Oswald-Richter, Kyra, Rosen, Michael J, Engelhardt, Brian G, Moore, Daniel J, Polk, D Brent
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.01.2013; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Age; Antibiotics; autoimmunity; B cell; Biological and medical sciences; Biomarkers - metabolism; Case-Control Studies; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - metabolism; cell signalling; cellular immunology; Crohn's disease; Cytokines; Enterocolitis, Necrotizing - immunology; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; FOXP3; Gangrene; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Profiling; gut immunology; gut inflammation; Humans; IBD; infant development; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases - immunology; Inflammatory bowel disease; Intensive care; intestinal development; Intestinal Mucosa - immunology; Lymphocyte Count; Lymphocytes; Male; Medical sciences; Mortality; mucosal immunity; mucosal immunology; Necrotising enterocolitis; neonatal gut; Other diseases. Semiology; Pathogenesis; Prospective Studies; Rodents; Small intestine; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; surgical resection; T lymphocytes; T-lymphocyte; T-Lymphocytes, Regulatory - metabolism; tolerance; Tumor necrosis factor-TNF; Human; Newborn; Immunological investigation; Mucosa; Gastroenterology; T-Lymphocyte; Digestive diseases; Intestinal disease; Necrotizing enterocolitis; Immune regulation; Effector
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2011-301551

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. Design 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. Conclusion 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.