The Neutrophil Respiratory Burst and Bacterial Digestion in Crohn's Disease

Department of Molecular Medicine, University College London, WC1E 6JJ, London, UK.
Digestive Diseases and Sciences (Impact Factor: 2.61). 10/2010; 56(5):1482-8. DOI: 10.1007/s10620-010-1426-8
Source: PubMed


Neutrophils are a key part of the innate immune defence against microbes, using the respiratory burst (RB) to optimise killing and digestion. Previous studies of the neutrophil RB in Crohn's disease (CD) have yielded conflicting results.
Superoxide production in response to phorbol-myristyl acetate (PMA) was measured in neutrophils from 100 patients with CD compared to 50 healthy controls (HCs) and 50 patients with ulcerative colitis (UC). A further 22 CD and 10 HCs were studied using f-Met-Leu-Phe (fMLP), and digestion of E. coli by neutrophils was also evaluated.
The mean ± SEM PMA-stimulated RB (nmol O(2)/10(6) cells/min) was 10.86 ± 0.26 in HCs, 9.76 ± 0.23 in CD (P=0.02) and 10.04 ± 0.28 in UC (P=0.09 vs HC and 0.47 vs CD). No significant effect of age, gender or medication was observed. The RB in three patients with presumed CD was found to be in the range expected in patients with inherited neutrophil disorders. Stimulation with fMLP was calcium dependent and attenuated in patients on 5-ASA. Digestion of E. coli by neutrophils was not different in HC vs CD (21.6 vs 20.53%, P=0.60).
The significant reduction in neutrophil RB in CD does not appear to result in defective bacterial digestion and is therefore unlikely play a major role in pathogenesis. Three patients in this cohort of patients with presumed idiopathic CD were found to have a profound defect of the neutrophil RB. A high index of suspicion for such patients is prudent, as their prognosis can be improved by altering or augmenting the conventional treatment regimens employed for CD.

Download full-text


Available from: Anthony W Segal, Jun 23, 2015
  • Source
    • "Loss of NADPH oxidase activity leads to reduced bactericidal activity of PMN, and defective ROS production in a number of inherited disorders is highly associated with intestinal inflammation that is undistinguishable from CD [48]. A recent study by Hayee et al. showed impaired fMLP-induced ROS production in CD PMN, but no defect in bacterial killing [20]. Whereas we confirmed the normal bacterial phagocytosis and killing, our study also demonstrated an enhanced fMLP-induced respiratory burst in CD PMN. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of the innate immunity in the pathogenesis of Crohn's disease (CD), an inflammatory bowel disease, is a subject of increasing interest. Neutrophils (PMN) are key members of the innate immune system which migrate to sites of bacterial infection and initiate the defence against microbes by producing reactive oxygen species (ROS), before undergoing apoptosis. It is believed that impaired innate immune responses contribute to CD, but it is as yet unclear whether intrinsic defects in PMN signal transduction and corresponding function are present in patients with quiescent disease. We isolated peripheral blood PMN from CD patients in remission and healthy controls (HC), and characterised migration, bacterial uptake and killing, ROS production and cell death signalling. Whereas IL8-induced migration and signalling were normal in CD, trans-epithelial migration was significantly impaired. Uptake and killing of E. coli were normal. However, an increased ROS production was observed in CD PMN after stimulation with the bacterial peptide analogue fMLP, which was mirrored by an increased fMLP-triggered ERK and AKT signal activation. Interestingly, cleavage of caspase-3 and caspase-8 during GMCSF-induced rescue from cell-death was decreased in CD neutrophils, but a reduced survival signal emanating from STAT3 and AKT pathways was concomitantly observed, resulting in a similar percentage of end stage apoptotic PMN in CD patients and HC. In toto, these data show a disturbed signal transduction activation and functionality in peripheral blood PMN from patients with quiescent CD, which point toward an intrinsic defect in innate immunity in these patients.
    Full-text · Article · Dec 2013 · PLoS ONE
  • Source

    Full-text · Article · Nov 2010 · Digestive Diseases and Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmunity is influenced by multiple factors including gender and sex hormones. A definite female predominance is found in many autoimmune diseases. Gender is also associated with differences in clinical presentation, onset, progression and outcome of autoimmune diseases. Sex hormones might influence the target organ's vulnerability to an autoimmune response. Gender differences also exist in organ specific autoimmune diseases such as multiple sclerosis, Guillain-Barré syndrome, Crohn's disease and celiac disease. Nevertheless, other organ specific autoimmune diseases (i.e. ulcerative colitis) are seemingly characterized with similar prevalence in both males and females. The reason for gender differences in certain autoimmune diseases remains unknown, but may be attributed to sex hormone influence, fetal microchimerism, X chromosome inactivation, and X chromosome abnormalities. Sex hormones have been found to have immune modulating properties, as well as providing cellular protection following tissue damage in certain circumstances. Sex hormones also influence innate and adaptive immune cells, number of B and T cells, antigen presentation and cytokine secretion. Herein, we review the influence of gender on organ-specific autoimmune diseases affecting the heart, blood vessels, central nervous system and gastrointestinal tract. It appears that sex hormones may have a therapeutic potential in several autoimmune conditions, although further research is required before therapeutic recommendations can be made.
    No preview · Article · Nov 2011 · Autoimmunity reviews
Show more