Insights into IBD Pathogenesis

Article · December 2009with20 Reads
DOI: 10.1007/s11894-009-0072-9 · Source: PubMed
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder caused by dysregulated immune responses in a genetically predisposed individual. Recent accumulating data, including genome-wide association studies, have identified more than 50 distinct genetic loci that confer susceptibility. We highlight the role of microbial-host interaction, particularly with respect to the overlap of common genetic and pathophysiologic mechanisms of CD and UC, interleukin-22-producing natural killer cells, autophagy, and TL1A, a member of the tumor necrosis factor (TNF) family, in gut homeostasis and IBD pathogenesis. This article focuses on the recent advances in understanding of IBD from the past year, including advances in genetics and immunobiology.
    • Polymorphisms in the TNFSF15 gene have been shown to contribute to the risk of both ulcerative colitis and Crohn's disease [59,60]. Increased expression of TL1A has been shown in Crohn's disease tissue [61], and antibody to TL1A prevents colitis development in mouse models [62]. In addition, mice overexpressing TL1A develop spontaneous intestinal inflammation [63,64].
    [Show abstract] [Hide abstract] ABSTRACT: Dysfunction of the mucosal immune system plays an important role in inflammatory bowel disease (IBD) pathogenesis. Dendritic cells are emerging as central players based on both our increasing understanding of how genetic susceptibility impacts the mucosal immune system and the key role of dendritic cells in regulating response to gut microflora. We discuss areas of therapeutic opportunity in this evolving landscape. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    Full-text · Article · Jan 2014
    • Inflammatory bowel disease (IBD) consists of two distinct diseases, Crohn's disease (CD) and ulcerative colitis (UC). Both diseases are thought to arise due to combination of genetic variations and alteration in bacterial flora which can subsequently drive a dysregulated immune response that results in chronic intestinal inflammation [1,2]. Interleukin 23 (IL-23) is a member of a small family of proinflammatory cytokine, consisting of a p19 subunit and a common p40 subunit [3].
    Article · Jan 2014 · Digestive Diseases and Sciences
    • Human inflammatory bowel diseases (IBD) are autoimmune diseases that are characterized by chronic autoinflammatory processes within the intestinal mucosal lamina propria. TNF has been demonstrated to play a key role in human IBD [11], [12], [13] and in experimental models of autoimmune colitis in mice [14], [15], where TNF induces intestinal epithelial cell apoptosis during intestinal inflammation, thereby aggravating the disease [16]. Of note, CD137L signaling has been demonstrated to induce TNF secretion [17], [18], and TNF receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling [19].
    [Show abstract] [Hide abstract] ABSTRACT: CD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. Expression of CD137 is upregulated in the lamina propria cells of Crohn's disease patients. Here, the role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined. We induced acute large bowel inflammation (colitis) via DSS administration in CD137(-/-) and wild-type (WT) mice. Colitis severity was evaluated by clinical parameters (weight loss), cytokine secretion in colon segment cultures, and scoring of histological inflammatory parameters. Additionally, populations of lamina propria mononuclear cells (LPMNC) and intraepithelial lymphocytes (IEL) were characterized by flow cytometry. In a subset of mice, resolution of intestinal inflammation was evaluated 3 and 7 days after withdrawal of DSS. We found that both CD137(-/-) and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure. However, the resolution of colonic inflammation was impaired in the absence of CD137. This was accompanied by a higher histological score of inflammation, and increased release of the pro-inflammatory mediators granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL1, IL-17 and IFN-γ. Further, there were significantly more neutrophils among the LPMNC of CD137(-/-) mice, and reduced numbers of macrophages among the IEL. We conclude that CD137 plays an essential role in the resolution of acute DSS-induced intestinal inflammation in mice.
    Full-text · Article · Sep 2013
    • The pathogenesis of IBDs is not completely understood , even if current theories hypothesize that IBD-related mucosal inflammation results from an exaggerated reaction of the mucosal immune system against components of the normal intestinal flora [1, 2] . No single infectious microorganism has been identified to cause these diseases, and genetic factors that confer susceptibility to IBDs are being unravelled [3] . Conventional treatments for IBD include corticosteroids , mesalamine, and thiopurines, therapies mostly aimed at blocking downstream inflammatory events.
    [Show abstract] [Hide abstract] ABSTRACT: Background To elucidate the effects of a solution containing interleukin-10 and anti-IL-1 antibody in modulating experimental intestinal inflammation. Methods Colitis was induced in BALB/c mice by oral administration of dextran sodium sulphate; mice were then treated with interleukin-10 plus anti-IL-1 antibody at low dosage. Transepithelial electrical resistance of isolated mouse colon and colon lengths were evaluated. Cytokines concentrations in organocultures supernatants and plasma samples were evaluated by Enzyme-Linked Immuno Sorbent Assay. Tight junction proteins were evaluated by immunofluorescence, respectively. Results Oral administration of tested products restores intestinal barrier function during experimental intestinal inflammation in association with reduced levels of proinflammatory cytokines, increased interleukin-10 plasma concentrations and a tight junction architecture restoration. Conclusion Obtained results may contribute to modelling an interesting strategy for the treatment of patients with inflammatory bowel diseases.
    Full-text · Article · Aug 2013
    • Crohn's disease (CD) is a chronic infl ammatory condition that predominately affects the gut with distinctive pathological features such as patchy transmural intestinal infl ammation, intestinal fi brostenosis and a dysregulated T helper (Th-) 1 and Th17 immune responses [1, 2]. Among the several recently discovered CD associated gene variants, a particular TNFSF15 haplotype is associated with higher TL1A expression, increased risk of CD, intestinal fi brostenosis, and greater need for surgery345.
    [Show abstract] [Hide abstract] ABSTRACT: TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell-dependent ileitis and fibrosis.
    Article · Mar 2013
    • Their etiopathogenesis is as yet incompletely understood, but is widely considered to involve an abnormal host immune response to an environmental stimulus (likely microbial) in a genetically predisposed individual [1]. CD and UC may cause similar symptoms, and share certain genetic susceptibility loci, but there are significant clinical differences between the diseases, and there is mounting evidence that their pathophysiology involves both overlapping and divergent pathways [2]. The emerging technique of ''metabonomics'' combines the acquisition of multiparametric metabolic data with multivariate pattern-recognition analysis [3, 4].
    [Show abstract] [Hide abstract] ABSTRACT: The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract whose pathogenesis is not completely understood. (1)H nuclear magnetic resonance (NMR) spectroscopy of serum generates comprehensive metabolic profiles, reflecting systemic metabolism, which may be altered in disease states. The aim of this study was to use (1)H NMR-based serum metabolic profiling in the investigation of CD patients, UC patients, and controls, potentially to provide insights into disordered metabolism in IBD, and into underlying mechanisms of disease. Serum metabolic profiles were acquired from 67 individuals (24 CD patients, 20 UC patients, and 23 healthy controls). The multivariate pattern-recognition techniques of principal components analysis (PCA) and partial least squares discriminant analysis with orthogonal signal correction (OSC-PLS-DA) were used to investigate differences between cohorts. OSC-PLS-DA distinguished CD and UC cohorts with significant predictive accuracy, highlighting differences in lipid and choline metabolism. Metabolic profiles of both CD and UC cohorts, and the combined IBD cohort, differed significantly from controls: metabolites of importance in the OSC-PLS-DA models included lipoproteins (especially HDL cholesterol), choline, N-acetylglycoprotein, and amino acids. (1)H NMR-based metabolic profiling has identified distinct differences in serum metabolic phenotype between CD and UC patients, as well as between IBD patients and controls.
    Full-text · Article · Apr 2012
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July 2009 · Biochimica et Biophysica Acta · Impact Factor: 4.66
Inflammatory bowel disease (IBD), a chronic inflammation of the gastrointestinal tract, is characterized by a deregulation of the mucosal immune system and resistance of activated T cells to apoptosis. Current therapeutics show limited efficacy and potential toxicity; therefore there is a need for novel approaches for the treatment of IBD. L-cysteine was examined for its ability to reduce... [Show full abstract]
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Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the... [Show full abstract]
July 2000 · Scandinavian Journal of Immunology · Impact Factor: 1.74
G-protein subunit Gαi2-deficient mice spontaneously develop an inflammatory bowel disease that clinically and histopathologically resembles ulcerative colitis in humans. The aim of this study was to determine whether immunological changes precede the development of colitis in Gαi2-deficient mice. Therefore, Gαi2-deficient mice with no clinical or histopathological signs of colitis were... [Show full abstract]
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Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract of unclear aetiology of which two major forms are Crohn's disease (CD) and ulcerative colitis (UC). CD and UC are immunologically distinct, although they both result from hyperactivation of proinflammatory pathways in intestines and disruption of intestinal epithelial barrier. Members of the... [Show full abstract]
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