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Pathology & Oncology Research
Published in: Pathology & Oncology Research 3/2011

01-09-2011 | Review

Cellular and Molecular Mechanisms in the Two Major Forms of Inflammatory Bowel Disease

Authors: Laszlo Bene, Andras Falus, Noemi Baffy, Andras Kristof Fulop

Published in: Pathology & Oncology Research | Issue 3/2011

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Abstract

The factors involved in the pathogenesis of Crohn’s disease and ulcerative colitis, the two major types of inflammatory bowel disease (IBD) are summarized. Intestinal antigens composed of bacterial flora along with antigen presentation and impaired mucosal barrier have an important role in the initiation of IBD. The bacterial community may be modified by the use of antibiotics and probiotics. The dentritic cells recognize the antigens by cell surface Toll like receptor and the cytoplasmic CARD/NOD system. The balance between Th1/Th2/Th17 cell populations being the source of a variety of cytokines regulates the inflammatory mechanisms and the clearance of microbes. The intracellular killing and digestion, including autophagy, are important in the protection against microbes and their toxins. The homing process determines the location and distribution of the immune cells along the gut. All these players are potential targets of pharmacological manipulation of disease status.
Literature
1.
2.
Balfour SR (2001) Induction of mucosal immune responses by bacteria and bacterial components. Curr Opin Gastroenterol 17:555–561CrossRef
3.
Mai V, Morris JG (2004) Colonic bacterial flora: changing understandings in the molecular age. J Nutr 134:459–464PubMed
4.
Wilson KH (2002) Natural biota of the human gastrointestinal tract. In: Blaser MJ, Smith PD, Ravdin JI (eds) gastrointestinal tract. Lippincott Williams & Wilkins, Philadelphia
5.
Danese S, Sans M, Fiocchi C (2004) Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 3:394–400PubMedCrossRef
6.
Cong Y, Weaver CT, Lazenby A et al (2002) Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol 169:6112–6119PubMed
7.
8.
Groux H, O'Garra A, Bigler M et al (1997) A CD4+ T-cell subset inhibits antigen specific T-cell responses and prevents colitis. Nature 389:737–742PubMedCrossRef
9.
Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793PubMedCrossRef
10.
Boirivant M, Marini M, Di Felice G et al (1999) Lamina propria T-cells in Crohn’s disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 116:557–565PubMedCrossRef
11.
Bu P, Keshavarzian A, Stone DD et al (2001) Apoptosis:one of the mechanisms that maintains unresponsivness of the intestinal mucosal immune system. J Immunol 166:6399–6403PubMed
12.
Nagler-Anderson C, Bober LA, Robinson ME et al (1986) Suppression of type II collagen- induced arthritis by intragastric administration of soluble type II. collagen. Proc Natl Acad Sci USA 83:7443–7446PubMedCrossRef
13.
Higgins PJ, Weiner HL (1988) Suppression of experimental encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 140:440–445PubMed
14.
Vrabec TR, Gregerson DS, Dua HS et al (1992) Inhibition of experimental autoimmun uveoretinitis by oral administration by oral administration of S-antigen and syntetic peptides. Autoimmunity 12:175–184PubMedCrossRef
15.
Neurath MF, Fuss I, Kelsall BL et al (2004) Experimental granulomatous colitis in mice abrogated by induction of TGF-β mediated oral tolerance. J Exp Med 183:2605–2616CrossRef
16.
Kraus TA, Toy L, Chan L et al (2004) Failure to induce oral tolerance in Crohn’s disease and ulcerative colitis patients: posible genetic risk. Ann NY Acad Sci 1029:225–238PubMedCrossRef
17.
Ilian Y (2004) Oral immune ragulation toward disease-assiciated antigens: results of phase I clinical trials in Crohn’s disease and chronic hepatitis. Ann NY Acad Sci 1029:286–298CrossRef
18.
Hart AL, Stagg AJ, Kamm MA (2003) Use of probiotics in the treatment of inflammatory bowel disease. J Clin Gastroenterol 36:111–119PubMedCrossRef
19.
Niess JH (2008) Role of mucosal dendritic cells in inflammatory bowel disease. World J Gastroenterol 14:5138–5148PubMedCrossRef
20.
Coombes JL, Maloy KJ (2007) Control of intestinal homeostasis by regulatory T-cells and dendritic cells. Semin Immunol 19:116–126PubMedCrossRef
21.
Iwasaki A, Kelsall BL (2001) Unique functions of CD11b+, CD8 alpha+, and double-negative Peyer’s patch dendritic cells. J Immunol 166:4884–4890PubMed
22.
Hart AL, Lammers K, Brigidi P et al (2004) Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53:1602–1609PubMedCrossRef
23.
Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303:1662–1665PubMedCrossRef
24.
Mora JR, Bono MR, Manjunath N et al (2003) Selective imrprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424:88–93PubMedCrossRef
25.
Krajina T, Leithäuser F, Möller P et al (2003) Colonic lamina propria dendritic cells in mice with CD4+ T cell-induced colitis. Eur J Immunol 33:1073–1083PubMedCrossRef
26.
Bell SJ, Rigby R, English N et al (2001) Migration and maturation of human colonic dendritic cells. J Immunol 166:4958–4967PubMed
27.
Rimoldi M, Chieppa M, Salucci V et al (2005) Intestinal immun homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 6:507–514PubMedCrossRef
28.
Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434PubMedCrossRef
29.
Suzuki M, Hisamatsu T, Podolsky DK (2003) Gamma interferon augments the intracellular pathway for lipopolysaccahride (LPS) recognition in human intestinal epithelial cells through coordinated upregulation of LPS uptake and expression of the intracellular Tolle-like receptor 4-MD-2 complex. Infect Immun 71:3503–3511PubMedCrossRef
30.
Ortega-Cava CF, Ishihara S, Rumi MA et al (2003) Strategic compertmentalization of toll-like receptor 4 in the mouse gut. J Immunol 170:3977–3985PubMed
31.
Abreu MT, Vora P, Faure E et al (2001) Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection adainst dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol 167:1609–1616PubMed
32.
Cario E, Podolsky DK (2000) Differencial alteration in intestinal epithelial cell expression of toll like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010–7017PubMedCrossRef
33.
Dubuquoy L, Jansson EA, Deeb S et al (2003) Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology 124:1265–1276PubMedCrossRef
34.
Frolova L, Drastich P, Rossmann P et al (2008) Expression of Toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. Histochem Cytochem 56:267–274CrossRef
35.
Lakatos PL, Kiss LS, Palatka K et al (2011) Serum lipopolysaccharide-binding protein and soluble CD14 are markers of disease activity in patients with Crohn’s disease. Inflamm Bowel Dis 17:767–777PubMedCrossRef
36.
Trinchieri G (2003) Interleukin-12 and regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146PubMedCrossRef
37.
Mosmann TR, Cherwinski H, Bond MW et al (1986) Two types of murine helper T cell clone. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMed
38.
Hayashi F, Smith KD, Ozinsky A et al (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103PubMedCrossRef
39.
Papp M, Altorjay I, Norman GL et al (2007) Seroreactivity to microbial components in Crohn’s disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm Bowel Dis 13:984–992PubMedCrossRef
40.
Abreu MT, Taylor KD, Lin YC et al (2002) Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 123:679–688PubMedCrossRef
41.
Szamosi T, Lakatos PL; Hungarian IBD Study Group et al (2009) The 3′UTR NFKBIA variant is associated with extensive colitis in Hungarian IBD patients. Dig Dis Sci 54:351–359CrossRef
42.
Hugot JP, Chamaillard M, Zouali H et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedCrossRef
43.
Chamaillard M, Philpott D, Girardin SE (2003) Gene enviroment interaction modulated by allelic heterogenety in inflammatory bowel diseases. Proc Natl Acad Sci USA 100:3455–3460PubMedCrossRef
44.
45.
Abreu MT, Arnold ET, Thomas LS et al (2002) TLR4 and MD-2 expression is regulated by immune medaited signals in human epithelial cells. J Biol Chem 277:20431–20437PubMedCrossRef
46.
Weigmann B, Nemetz A, Becker C et al (2004) A critical regulatory role of leucin zipper transcription factor c-Maf in Th1-mediated experimental colitis. J Immunol 173:3446–3455PubMed
47.
Elson CO, Cong Y, Iqbal N et al (2001) Immuno-bacterial homeostasis in gut: new insight into the old enigma. Semin Immunol 13:187–194PubMedCrossRef
48.
Boirivant M, Fuss IJ, Chu A et al (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188:1929–1939PubMedCrossRef
49.
Maeda S, Hsu LC, Liu H et al (2005) Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science 307:734–738PubMedCrossRef
50.
Girardin SE, Boneca IG, Carneiro LA et al (2003) Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300:1584–1587PubMedCrossRef
51.
Lala S, Ogura Y, Osborne C et al (2003) Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology 125:47–57PubMedCrossRef
52.
Ramasundara M, Leach ST, Lemberg DA, Day AS (2009) Defensins and inflammation: the role of defensins in inflammatory bowel disease. J Gastroenterol Hepatol 24:202–208PubMedCrossRef
53.
Inohara N, Ogura Y, Fontalba A et al (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 278:5509–5512PubMedCrossRef
54.
Berrebi D, Maudinas R, Hugot JP et al (2003) Card15 gene overexpression in mononuclear and epithelial cells of the inflammed Crohn’s disease colon. Gut 52:840–846PubMedCrossRef
55.
Hisamatsu T, Suzuki M, Reinecker HC (2003) CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 24:1001–1009
56.
Brimnes J, Reimann J, Nissen M et al (2001) Enteric bacterial antigens activate CD4(+) T cells from scid mice with inflammatory bowel disease. Eur J Immunol 31:23–31PubMedCrossRef
57.
Peluso I, Pallone F, Monteleone G (2006) Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol 12:5606–5610PubMed
58.
Neurath MF, Weigmann B, Finotto S et al (2002) The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Cronh’s disease. J Exp Med 195:1129–1143PubMedCrossRef
59.
Afkarian M, Sedy JR, Yang J et al (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol 3:506–508CrossRef
60.
Heller F, Fuss IJ, Nieuwenhuis EE et al (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638PubMedCrossRef
61.
Pastorelli L, Garg RR, Hoang SB et al (2010) Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S 107:8017–8022CrossRef
62.
Levy DE, Lee CK (2002) What does Stat3 do? J Clin Invest 109:1143–1148PubMed
63.
Mudter J, Weigmann B, Bartsch B et al (2005) Activation pattern of signal transducer and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol 100:64–72PubMedCrossRef
64.
Shull MM, Ormsby I, Kier AB et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699PubMedCrossRef
65.
Babyatsky MW, Rossiter G, Podolsky DK (1996) Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology 110:975–984PubMedCrossRef
66.
Yamaguchi T, Ihara K, Matsumoto T et al (2001) Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. Inflamm Bowel Dis 7:128–132PubMedCrossRef
67.
Weaver CT, Hatton RD, Mangan PR et al (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:851–852CrossRef
68.
Kastelein RA, Hunter CA, Cua DJ (2007) Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 25:221–242PubMedCrossRef
69.
Ivanov II, McKenzie BS, Zhou L et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133PubMedCrossRef
70.
Langrish CL, Chen Y, Blumenschein WM et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240PubMedCrossRef
71.
Zhou L, Lopes JE, Chong MM et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240PubMedCrossRef
72.
Shen W, Durum SK (2010) Synergy of IL-23 and Th17 cytokines: new light on inflammatory bowel disease. Neurochem Res 35:940–946PubMedCrossRef
73.
Bettelli E, Oukka M, Kuchroo VK (2007) TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350PubMedCrossRef
74.
Kinugasa T, Sakaguchi T, Gu X et al (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118:1001–1011PubMedCrossRef
75.
Rioux JD, Xavier RJ, Taylor KD et al (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596–604PubMedCrossRef
76.
Ellson CD, Davidson K, Ferguson GJ et al (2006) Neutrophils from p40phox2/2 mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J Exp Med 203:1927–1937PubMedCrossRef
77.
Ogawa M, Yoshimori T, Suzuki T, Sagara H et al (2004) Escape of intracellular Shigella from autophagy. Science 307:727–731PubMedCrossRef
78.
Lakatos PL, Szamosi T, Szilvasi A et al (2008) ATG16L1 and IL23 receptor (IL23R) genes are associated with disease susceptibility in Hungarian CD patients. Dig Liver Dis 40:867–873PubMedCrossRef
79.
Hampe J, Franke A, Rosenstiel P et al (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39:207–211PubMedCrossRef
80.
Parkes M, Barrett JC, Prescott NJ et al (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39:830–832PubMedCrossRef
81.
Singh SB, Davis AS, Taylor G et al (2006) IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:1438–1441PubMedCrossRef
82.
Taylor GA (2007) IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell Microbiol 9:1099–1107PubMedCrossRef
83.
Mäkitalo L, Kolho KL, Karikoski R et al (2010) Expression profiles of matrix metalloproteinases and their inhibitors in colonic inflammation related to pediatric inflammatory bowel disease. Scand J Gastroenterol 45:862–871PubMedCrossRef
84.
Salmi M, Andrew DP, Butcher EC et al (1995) Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J Exp Med 181:137–149PubMedCrossRef
85.
Bernstein CN, Sargent M, Rector E (2002) Alteration in expression of beta 2 integrins on lamina propria lymphocytes in ulcerative colitis and Crohn’s disease. Clin Immunol 104:67–72PubMedCrossRef
Metadata
Title
Cellular and Molecular Mechanisms in the Two Major Forms of Inflammatory Bowel Disease
Authors
Laszlo Bene
Andras Falus
Noemi Baffy
Andras Kristof Fulop
Publication date
01-09-2011
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 3/2011
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-011-9397-4

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