There are now many experimental models of inflammatory bowel disease (IBD), most of which are due to induced mutations in mice that result in an impaired homeostasis with the intestinal microbiota. These models can be clustered into several broad categories that, in turn, define the crucial cellular and molecular mechanisms of host microbial interactions in the intestine. The first of these components is innate immunity defined broadly to include both myeloid and epithelial cell mechanisms. A second component is the effector response of the adaptive immune system, which, in most instances, comprises the CD4+ T cell and its relevant cytokines. The third component is regulation, which can involve multiple cell types, but again particularly involves CD4+ T cells. Severe impairment of a single component can result in disease, but many models demonstrate milder defects in more than one component. The same is true for both spontaneous models of IBD, C3H/HeJBir and SAMPI/Yit mice. The thesis is advanced that 'multiple hits' or defects in these interacting components is required for IBD to occur in both mouse and human.
Background & Aims-Premature neonates are predisposed to necrotizing enterocolitis (NEC), an idiopathic, inflammatory bowel necrosis. We investigated the hypothesis that NEC occurs in the preterm intestine due to incomplete 'non-inflammatory' differentiation of intestinal macrophages, which increases the risk of a severe mucosal inflammatory response to bacterial products.
The type of operation performed for perforated necrotizing enterocolitis does not influence survival or other clinically important early outcomes in preterm infants. (ClinicalTrials.gov number, NCT00252681.).
After adjusting for known predictors of mortality, AKI and RRT independently predict mortality in neonates and children, who receive extracorporeal membrane oxygenation. Ascertainment of AKI risk factors, testing novel therapies, and optimizing the timing/delivery of RRT may positively impact survival.
Background
The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.
Methods
Data on 104 extremely low birth weight (ELBW) infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.
Results
Male gender, non-Caucasian/non-African-American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand (CCL)-2, macrophage inflammatory protein-1β/CCL3, and C-reactive protein.
Conclusions
Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.
Objectives
Therapy with broad-spectrum antibiotics is a common practice for premature infants. This treatment can reduce the biodiversity of the fecal microbiota and may be a factor in the cause of necrotizing enterocolitis (NEC). In contrast, probiotic treatment of premature infants reduces the incidence of NEC. We hypothesized that one mechanism for these observations is the influence of bacteria on postnatal development of the mucosal immune system.
Methods
Expression of immune molecules and microbial sensors was investigated in the postnatal mouse gastrointestinal tract by real-time PCR. Subsequently, two-week-old specific pathogen free (SPF) and microbial reduced (antibiotic treated, MR) mice were compared for immune molecule and microbial sensor expression, mesenteric lymph node (MLN) T-cell numbers and activation, intestinal barrier function/permeability, systemic lymphocyte numbers, and T-cell phenotype commitment.
Results
Toll-like receptor (TLR) 2, 4, and 5 expression was highest in 2-week-old SPF mice, and this expression was decreased in MR mice. There was no difference in intestinal tight-junctional function, as evaluated by FITC-dextran uptake, but MR mice had increased bacteria translocation across the intestinal epithelial barrier. MR mice had significantly fewer splenic B-cells and MLN CD4+ T-cells, but there were normal numbers of splenic T-cells. These systemic T-cells from MR mice produced more IL-4, and less interferon-γ and IL-17, indicative of a maintenance of the fetal, T-helper cell type 2 phenotype.
Conclusions
This study shows that intestinal commensal microbiota have an influence on early postnatal immune development. Determining specific bacteria and/or bacterial ligands critical for this development could provide insight into the mechanisms by which broad-spectrum antibiotics and/or probiotic therapy influences the development of the mucosal immune system and mucosal-related diseases.
Frequently fatal, primary hemophagocytic lymphohistiocytosis (HLH) occurs in infancy resulting from homozygous mutations in natural killer (NK) and CD8 T cell cytolytic pathway genes. Secondary HLH presents after infancy and may be associated with heterozygous mutations in HLH genes. We report 2 unrelated teenagers with HLH and an identical heterozygous RAB27A mutation (c.259G>C). We explore the contribution of this Rab27A missense (p.A87P) mutation on NK cell cytolytic function by cloning it into a lentiviral expression vector prior to introduction into the human NK-92 cell line. NK cell degranulation (CD107a expression), target cell conjugation, and K562 target cell lysis was compared between mutant and wild-type transduced NK-92 cells. Polarization of granzyme B to the immunologic synapse and interaction of mutant Rab27A (p.A87P) with Munc13-4 were explored by confocal microscopy and proximity ligation assay, respectively. Over-expression of the RAB27A mutation had no effect on cell conjugate formation between the NK and target cells but decreased NK cell cytolytic activity and degranulation. Moreover, the mutant Rab27A protein decreased binding to Munc13-4 and delayed granzyme B polarization towards the immunologic synapse. This heterozygous RAB27A mutation blurs the genetic distinction between primary and secondary HLH by contributing to HLH via a partial dominant-negative effect.
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