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. 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.

Proteobacteria-specific IgA regulates maturation of the intestinal microbiota

“…[6][7][8] Altered control of intestinal bacteria in adults can also result in intestinal inflammation and carcinogenesis. 9 Mouse models for intestinal inflammation have revealed several key factors that are involved in maintenance of homeostatic interactions of the host with intestinal bacteria.…”

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

“…The fact that NEC usually occurs at least a week after birth and after the initiation of enteral feedings is consistent with the idea that the adaptive immune system is also of significance. In a recent human study, premature infants with NEC were shown to have a significantly reduced ratio of T regulatory cells (Tregs) to effector T cells (CD4 + and CD8 + , Teffs) compared to gestational age-matched controls (8). Furthermore, adoptive transfer of Tregs harvested from adult rats have been shown to protect NEC-induced pups against severe intestinal damage (9).…”

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

“…Innate and adaptive immune responses are activated after hypoxic ischemic injury, leading to brain inflammation, perpetuated by eventual perinatal infection and inflammation [82]. A robust cerebral immune response, characterized by an imbalance between the pro-inflammatory Th1/ Th17-and the anti-inflammatory Th2/Treg-type responses, has been documented in animal models of white matter injury [35] (Table 1).…”

“…Moreover, following intrauterine inflammation, the fetal Th1/Th2 ratio shifts towards Th1 cells, with a corresponding increase in interferon-gamma (IFN-γ) [33]. Interestingly, several neonatal diseases are characterized by a pro-inflammatory state due to excessive pro-inflammatory lymphocyte subsets (Th1, Th17) and deficient representation in Tregs [34][35][36] (Table 1).…”

“…This confirms the notion that MSCs are most effective when administered in the context of inflammation. Accordingly, the combined administration of both ↑ in murine HI cerebral tissue [37] ↑ Th1 and Th17 in murine HI cerebral tissue [34] ↓ Treg in murine HI cerebral tissue [34] BPD ↓ M1 macrophages in murine lung [38] ↓M2 macrophages in murine lung [38] ↓ activated DCs in murine and human lung [39,40] Unchanged in murine lung [38] ↓ Th1 and Th17 in peripheral blood during the first week of life in BPD patients [41] ↓ Treg in cord blood in BPD patients [36] NEC ↓ M1 macrophages in murine NEC tissue [42] Unknown ↓ Th17 in human NEC tissue [35] ↓Treg in human NEC tissue [35] Periventricular leukomalacia (PVL), Hypoxic ischemic encephalopathy (HIE), Bronchopulmonary dysplasia (BPD), Necrotising enterocolitis (NEC), Lymphocytes T helper (Th), cerebrospinal fluid (CSF), Denditric cells (DCs), Hypoxia-ischemia (HI)…”