New Concepts in the Pathophysiology of Inflammatory Bowel Disease (2005)

Reviews20 December 2005New Concepts in the Pathophysiology of Inflammatory Bowel DiseaseGiorgos Bamias, MD, Mark R. Nyce, MD, Sarah A. De La Rue, PhD, and Fabio Cominelli, MD, PhDGiorgos Bamias, MDFrom University of Virginia, Charlottesville, Virginia., Mark R. Nyce, MDFrom University of Virginia, Charlottesville, Virginia., Sarah A. De La Rue, PhDFrom University of Virginia, Charlottesville, Virginia., and Fabio Cominelli, MD, PhDFrom University of Virginia, Charlottesville, Virginia.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-143-12-200512200-00007 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical PrinciplesThe inflammatory bowel diseases (IBDs), that is, Crohn disease and ulcerative colitis, affect approximately 1 million persons in North America and several million persons worldwide.Approximately 30% of patients present between 10 and 30 years of age.Current therapeutic options are limited and include nonspecific anti-inflammatory and immunosuppresive medications.Surgery is required for 50% to 80% of patients with Crohn disease, while only 20% of patients with ulcerative colitis have surgery.Novel biological therapeutics have greatly improved the quality of life of patients with IBD.Pathophysiologic PrinciplesBoth genetic and environmental factors play important roles in disease pathogenesis.New hypotheses implicate the innate immune system and ...References1. Cominelli F. Cytokine-based therapies for Crohn's disease—new paradigms. N Engl J Med. 2004;351:2045-8. [PMID: 15537904] CrossrefMedlineGoogle Scholar2. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521-33. [PMID: 12876555] CrossrefMedlineGoogle Scholar3. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115:182-205. [PMID: 9649475] CrossrefMedlineGoogle Scholar4. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417-29. [PMID: 12167685] CrossrefMedlineGoogle Scholar5. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495-549. [PMID: 11861611] CrossrefMedlineGoogle Scholar6. Pizarro TT, Arseneau KO, Bamias G, Cominelli F. Mouse models for the study of Crohn's disease. Trends Mol Med. 2003;9:218-22. [PMID: 12763527] CrossrefMedlineGoogle Scholar7. Fuss IJ, Boirivant M, Lacy B, Strober W. The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J Immunol. 2002;168:900-8. [PMID: 11777988] CrossrefMedlineGoogle Scholar8. Strober W, Kelsall B, Fuss I, Marth T, Ludviksson B, Ehrhardt R, et al. Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today. 1997;18:61-4. [PMID: 9057354] CrossrefMedlineGoogle Scholar9. Abreu MT, Arditi M. Innate immunity and toll-like receptors: clinical implications of basic science research. J Pediatr. 2004;144:421-9. [PMID: 15069387] CrossrefMedlineGoogle Scholar10. Reuter BK, Pizarro TT. Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? Eur J Immunol. 2004;34:2347-55. [PMID: 15307167] CrossrefMedlineGoogle Scholar11. Bonen DK, Cho JH. The genetics of inflammatory bowel disease. Gastroenterology. 2003;124:521-36. [PMID: 12557156] CrossrefMedlineGoogle Scholar12. Duerr RH. Update on the genetics of inflammatory bowel disease. J Clin Gastroenterol. 2003;37:358-67. [PMID: 14564181] CrossrefMedlineGoogle Scholar13. Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP. Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther. 2001;15:731-48. [PMID: 11380312] CrossrefMedlineGoogle Scholar14. Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature. 1996;379:821-3. [PMID: 8587604] CrossrefMedlineGoogle Scholar15. Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet. 2001;68:1165-71. [PMID: 11309682] CrossrefMedlineGoogle Scholar16. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599-603. [PMID: 11385576] CrossrefMedlineGoogle Scholar17. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603-6. [PMID: 11385577] CrossrefMedlineGoogle Scholar18. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet. 2001;357:1925-8. [PMID: 11425413] CrossrefMedlineGoogle Scholar19. Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002;122:867-74. [PMID: 11910337] CrossrefMedlineGoogle Scholar20. Eckmann L, Karin M. NOD2 and Crohn's disease: loss or gain of function? Immunity. 2005;22:661-7. [PMID: 15963781] CrossrefMedlineGoogle Scholar21. Bevins CL. The Paneth cell and the innate immune response. Curr Opin Gastroenterol. 2004;20:572-80. [PMID: 15703685] CrossrefMedlineGoogle Scholar22. Yu Y, Sitaraman S, Gewirtz AT. Intestinal epithelial cell regulation of mucosal inflammation. Immunol Res. 2004;29:55-68. [PMID: 15181270] CrossrefMedlineGoogle Scholar23. Panwala CM, Jones JC, Viney JL. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol. 1998;161:5733-44. [PMID: 9820555] MedlineGoogle Scholar24. Hermiston ML, Gordon JI. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science. 1995;270:1203-7. [PMID: 7502046] CrossrefMedlineGoogle Scholar25. Mennechet FJ, Kasper LH, Rachinel N, Li W, Vandewalle A, Buzoni-Gatel D. Lamina propria CD4+ T lymphocytes synergize with murine intestinal epithelial cells to enhance proinflammatory response against an intracellular pathogen. J Immunol. 2002;168:2988-96. [PMID: 11884471] CrossrefMedlineGoogle Scholar26. Kwon JH, Keates S, Bassani L, Mayer LF, Keates AC. Colonic epithelial cells are a major site of macrophage inflammatory protein 3alpha (MIP-3alpha) production in normal colon and inflammatory bowel disease. Gut. 2002;51:818-26. [PMID: 12427784] CrossrefMedlineGoogle Scholar27. Stadnyk AW. Intestinal epithelial cells as a source of inflammatory cytokines and chemokines. Can J Gastroenterol. 2002;16:241-6. [PMID: 11981577] CrossrefMedlineGoogle Scholar28. Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157:1261-70. [PMID: 8757634] MedlineGoogle Scholar29. Gor DO, Rose NR, Greenspan NS. TH1-TH2: a procrustean paradigm. Nat Immunol. 2003;4:503-5. [PMID: 12774069] CrossrefMedlineGoogle Scholar30. Bullens DM, Kasran A, Thielemans K, Bakkus M, Ceuppens JL. CD40L-induced IL-12 production is further enhanced by the Th2 cytokines IL-4 and IL-13. Scand J Immunol. 2001;53:455-63. [PMID: 11309153] CrossrefMedlineGoogle Scholar31. Fort M, Lesley R, Davidson N, Menon S, Brombacher F, Leach M, et al. IL-4 exacerbates disease in a Th1 cell transfer model of colitis. J Immunol. 2001;166:2793-800. [PMID: 11160346] CrossrefMedlineGoogle Scholar32. Garside P. Cytokines in experimental colitis [Editorial]. Clin Exp Immunol. 1999;118:337-9. [PMID: 10594548] CrossrefMedlineGoogle Scholar33. O'Shea JJ, Ma A, Lipsky P. Cytokines and autoimmunity. Nat Rev Immunol. 2002;2:37-45. [PMID: 11905836] CrossrefMedlineGoogle Scholar34. Pedotti R, De Voss JJ, Steinman L, Galli SJ. Involvement of both "allergic" and "autoimmune" mechanisms in EAE, MS and other autoimmune diseases. Trends Immunol. 2003;24:479-84. [PMID: 12967671] CrossrefMedlineGoogle Scholar35. Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology. 2000;119:1473-82. [PMID: 11113068] CrossrefMedlineGoogle Scholar36. Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology. 2000;119:1461-72. [PMID: 11113067] CrossrefMedlineGoogle Scholar37. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997;337:1029-35. [PMID: 9321530] CrossrefMedlineGoogle Scholar38. Armuzzi A, De Pascalis B, Lupascu A, Fedeli P, Leo D, Mentella MC, et al. Infliximab in the treatment of steroid-dependent ulcerative colitis. Eur Rev Med Pharmacol Sci. 2004;8:231-3. [PMID: 15638236] MedlineGoogle Scholar39. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis. 2005;11:213-8. [PMID: 15735427] CrossrefMedlineGoogle Scholar40. Kohn A, Prantera C, Pera A, Cosintino R, Sostegni R, Daperno M. Infliximab in the treatment of severe ulcerative colitis: a follow-up study. Eur Rev Med Pharmacol Sci. 2004;8:235-7. [PMID: 15638237] MedlineGoogle Scholar41. Tsukada Y, Nakamura T, Iimura M, Iizuka BE, Hayashi N. Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis. Am J Gastroenterol. 2002;97:2820-8. [PMID: 12425554] CrossrefMedlineGoogle Scholar42. Becher B, Durell BG, Noelle RJ. IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J Clin Invest. 2003;112:1186-91. [PMID: 14561703] CrossrefMedlineGoogle Scholar43. Becker C, Wirtz S, Blessing M, Pirhonen J, Strand D, Bechthold O, et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J Clin Invest. 2003;112:693-706. [PMID: 12952918] CrossrefMedlineGoogle Scholar44. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715-25. [PMID: 11114383] CrossrefMedlineGoogle Scholar45. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity. 2002;16:779-90. [PMID: 12121660] CrossrefMedlineGoogle Scholar46. Bamias G, Martin C, Marini M, Hoang S, Mishina M, Ross WG, et al. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol. 2003;171:4868-74. [PMID: 14568967] CrossrefMedlineGoogle Scholar47. Prehn JL, Mehdizadeh S, Landers CJ, Luo X, Cha SC, Wei P, et al. Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol. 2004;112:66-77. [PMID: 15207783] CrossrefMedlineGoogle Scholar48. Pelletier M, Bouchard A, Girard D. In vivo and in vitro roles of IL-21 in inflammation. J Immunol. 2004;173:7521-30. [PMID: 15585879] CrossrefMedlineGoogle Scholar49. Mehta DS, Wurster AL, Grusby MJ. Biology of IL-21 and the IL-21 receptor. Immunol Rev. 2004;202:84-95. [PMID: 15546387] CrossrefMedlineGoogle Scholar50. Kosiewicz MM, Nast CC, Krishnan A, Rivera-Nieves J, Moskaluk CA, Matsumoto S, et al. Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J Clin Invest. 2001;107:695-702. [PMID: 11254669] CrossrefMedlineGoogle Scholar51. Rivera-Nieves J, Bamias G, Vidrich A, Marini M, Pizarro TT, McDuffie MJ, et al. Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis. Gastroenterology. 2003;124:972-82. [PMID: 12671894] CrossrefMedlineGoogle Scholar52. Bamias G, Martin C, Mishina M, Ross WG, Rivera-Nieves J, Marini M, et al. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology. 2005;128:654-66. [PMID: 15765401] CrossrefMedlineGoogle Scholar53. Rivera-Nieves J, Olson T, Bamias G, Bruce A, Solga M, Knight RF, et al. L-selectin, alpha 4 beta 1, and alpha 4 beta 7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine. J Immunol. 2005;174:2343-52. [PMID: 15699171] CrossrefMedlineGoogle Scholar54. Desreumaux P, Brandt E, Gambiez L, Emilie D, Geboes K, Klein O, et al. Distinct cytokine patterns in early and chronic ileal lesions of Crohn's disease. Gastroenterology. 1997;113:118-26. [PMID: 9207269] CrossrefMedlineGoogle Scholar55. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology. 2000;119:895-902. [PMID: 11040176] CrossrefMedlineGoogle Scholar56. Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease. Am J Gastroenterol. 2000;95:3189-94. [PMID: 11095340] CrossrefMedlineGoogle Scholar57. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev. 2004;3:394-400. [PMID: 15288007] CrossrefMedlineGoogle Scholar58. Linskens RK, Huijsdens XW, Savelkoul PH, Vandenbroucke-Grauls CM, Meuwissen SG. The bacterial flora in inflammatory bowel disease: current insights in pathogenesis and the influence of antibiotics and probiotics. Scand J Gastroenterol Suppl. 2001;:29-40. [PMID: 11768558] CrossrefMedlineGoogle Scholar59. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620-33. [PMID: 15168372] CrossrefMedlineGoogle Scholar60. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113:1296-306. [PMID: 15124021] CrossrefMedlineGoogle Scholar61. Sutton CL, Kim J, Yamane A, Dalwadi H, Wei B, Landers C, et al. Identification of a novel bacterial sequence associated with Crohn's disease. Gastroenterology. 2000;119:23-31. [PMID: 10889151] CrossrefMedlineGoogle Scholar62. Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. Gastroenterology. 2004;126:414-24. [PMID: 14762777] CrossrefMedlineGoogle Scholar63. Arnott ID, Landers CJ, Nimmo EJ, Drummond HE, Smith BK, Targan SR, et al. Sero-reactivity to microbial components in Crohn's disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol. 2004;99:2376-84. [PMID: 15571586] CrossrefMedlineGoogle Scholar64. Mow WS, Landers CJ, Steinhart AH, Feagan BG, Croitoru K, Seidman E, et al. High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn's disease: a pilot study. Dig Dis Sci. 2004;49:1280-6. [PMID: 15387358] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From University of Virginia, Charlottesville, Virginia.Acknowledgments: The authors thank the entire personnel of the Digestive Health Center of Excellence at the University of Virginia.Grant Support: By the United States Public Health Service/National Institutes of Health grants DK-42195, DK-44540, and DK-55812 to Fabio Cominelli and The UVa Digestive Health Research Center (P30 DK-67629).Disclosures: Honoraria: F. Cominelli (UCB Pharmaceuticals, Inc., Centocor, Elan, Sigma-Tau).Corresponding Author: Fabio Cominelli, MD, PhD, Division of Gastroenterology and Hepatology, P.O. Box 800708, University of Virginia Health System, Charlottesville, VA 22908; e-mail, [email protected]edu.Current Author Addresses: Drs. Bamias, Nyce, De La Rue, and Cominelli: Digestive Health Center of Excellence, University of Virginia, P.O. Box 800708, Charlottesville, VA 22908-0708. 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