Journal of Gastroenterology

, Volume 45, Issue 1, pp 9–16 | Cite as

Evolving paradigms in the pathogenesis of IBD



The pathogenesis of all immune-mediated inflammatory diseases has been carefully studied over the past several decades, but it is only recently that we have come to appreciate common pathways and genes. This is especially true for the inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis, where a keener appreciation of the contributions of genetics, environment, and immune response have been dissected. In fact, in many ways, IBD has become the model for studying such disorders. The complex nature of interactions is continuing to be defined, and novel therapies targeting defects in these interactions have been developed and are being tested in the clinic. The era of bench to bedside has finally matured, and cures for debilitating diseases are now in sight. This review describes our current state of knowledge of each component of IBD pathogenesis. What has evolved is a clearer picture and novel targets for therapy.


Inflammatory bowel diseases Crohn’s disease Ulcerative colitis Pathogenesis 


  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.CrossRefPubMedGoogle Scholar
  3. 3.
    Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004;36:471–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73:1282–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596–604.CrossRefPubMedGoogle Scholar
  7. 7.
    Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Podolsky DK. Lessons from genetic models of inflammatory bowel disease. Acta Gastroenterol Belg. 1997;60:163–5.PubMedGoogle Scholar
  9. 9.
    Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514–21.CrossRefPubMedGoogle Scholar
  10. 10.
    Braun J, Targan SR. Multiparameter analysis of immunogenetic mechanisms in clinical diagnosis and management of inflammatory bowel disease. Adv Exp Med Biol. 2006;579:209–18.CrossRefPubMedGoogle Scholar
  11. 11.
    Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;102:448–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Mowat AM, Viney JL. The anatomical basis of intestinal immunity. Immunol Rev. 1997;156:145–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128:1868–78.CrossRefPubMedGoogle Scholar
  14. 14.
    Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+ CD25+ regulatory T cells. J Immunol. 2003;170:3939–43.PubMedGoogle Scholar
  15. 15.
    Brimnes J, Allez M, Dotan I, Shao L, Nakazawa A, Mayer L. Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease. J Immunol. 2005;174:5814–22.PubMedGoogle Scholar
  16. 16.
    Sachar DB. Genomics and phenomics in Crohn’s disease. Gastroenterology. 2002;122:1161–2.CrossRefPubMedGoogle Scholar
  17. 17.
    Spencer DM, Veldman GM, Banerjee S, Willis J, Levine AD. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology. 2002;122:94–105.CrossRefPubMedGoogle Scholar
  18. 18.
    Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology. 2004;126:1593–610.CrossRefPubMedGoogle Scholar
  19. 19.
    Halme L, Paavola-Sakki P, Turunen U, Lappalainen M, Farkkila M, Kontula K. Family and twin studies in inflammatory bowel disease. World J Gastroenterol. 2006;12:3668–72.PubMedGoogle Scholar
  20. 20.
    Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35:1075–81.CrossRefPubMedGoogle Scholar
  21. 21.
    Satsangi J, Parkes M, Jewell DP, Bell JI. Genetics of inflammatory bowel disease. Clin Sci (Lond). 1998;94:473–8.Google Scholar
  22. 22.
    Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. Am J Gastroenterol. 2006;101:993–1002.CrossRefPubMedGoogle Scholar
  23. 23.
    Brant SR, Shugart YY. Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Inflamm Bowel Dis. 2004;10:300–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Esters N, Pierik M, van Steen K, Vermeire S, Claessens G, Joossens S, et al. Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease. Am J Gastroenterol. 2004;99:299–305.CrossRefPubMedGoogle Scholar
  25. 25.
    Weiss B, Shamir R, Bujanover Y, Waterman M, Hartman C, Fradkin A, et al. NOD2/CARD15 mutation analysis and genotype-phenotype correlation in Jewish pediatric patients compared with adults with Crohn’s disease. J Pediatr. 2004;145:208–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Abreu MT, Taylor KD, Lin YC, Hang T, Gaiennie J, Landers CJ, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology. 2002;123:679–88.CrossRefPubMedGoogle Scholar
  27. 27.
    Halfvarson J, Bodin L, Tysk C, Lindberg E, Jarnerot G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology. 2003;124:1767–73.CrossRefPubMedGoogle Scholar
  28. 28.
    Halfvarson J, Jess T, Bodin L, Jarnerot G, Munkholm P, Binder V, et al. Longitudinal concordance for clinical characteristics in a Swedish–Danish twin population with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:1536–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Chiba M, Fukushima T, Horie Y, Iizuka M, Masamune O. No Mycobacterium paratuberculosis detected in intestinal tissue, including Peyer’s patches and lymph follicles, of Crohn’s disease. J Gastroenterol. 1998;33:482–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Drossman DA. Presidential address: gastrointestinal illness and the biopsychosocial model. Psychosom Med. 1998;60:258–67.PubMedGoogle Scholar
  31. 31.
    Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev. 2000;173:89–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994;76:275–85.CrossRefPubMedGoogle Scholar
  33. 33.
    Medzhitov R, Janeway CA Jr. Innate immune recognition and control of adaptive immune responses. Semin Immunol. 1998;10:351–3.CrossRefPubMedGoogle Scholar
  34. 34.
    Huang JS, Noack D, Rae J, Ellis BA, Newbury R, Pong AL, et al. Chronic granulomatous disease caused by a deficiency in p47(phox) mimicking Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:690–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP. Hermansky–Pudlak syndrome with granulomatous colitis. Ann Int Med. 1980;92:20–3.PubMedGoogle Scholar
  36. 36.
    Dieckgraefe BK, Korzenik JR. Treatment of active Crohn’s disease with recombinant human granulocyte–macrophage colony-stimulating factor. Lancet. 2002;360:1478–80.CrossRefPubMedGoogle Scholar
  37. 37.
    Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, Binion DG, et al. Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut. 2007;56:1696–705.CrossRefPubMedGoogle Scholar
  38. 38.
    Brown SJ, Mayer L. The immune response in inflammatory bowel disease. Am J Gastroenterol. 2007;102:2058–69.CrossRefPubMedGoogle Scholar
  39. 39.
    Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–7.PubMedGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    van Assche G. Emerging drugs to treat Crohn’s disease. Expert Opin Emerg Drugs. 2007;12:49–59.CrossRefPubMedGoogle Scholar
  42. 42.
    Kobayashi K, Kaneda K, Kasama T. Immunopathogenesis of delayed-type hypersensitivity. Microsc Res Tech. 2001;53:241–5.CrossRefPubMedGoogle Scholar
  43. 43.
    Glimcher LH. Trawling for treasure: tales of T-bet. Nat Immunol. 2007;8:448–50.CrossRefPubMedGoogle Scholar
  44. 44.
    Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74:185–95.CrossRefPubMedGoogle Scholar
  45. 45.
    MacDonald TT, Bajaj-Elliott M, Pender SL. T cells orchestrate intestinal mucosal shape and integrity. Immunol Today. 1999;20:505–10.CrossRefPubMedGoogle Scholar
  46. 46.
    Alber G, Al-Robaiy S, Kleinschek M, Knauer J, Krumbholz P, Richter J, Schoeneberger S, Schuetze N, Schulz S, Toepfer K, Voigtlaender R, Lehmann J, Mueller U. Induction of immunity and inflammation by interleukin-12 family members. Ernst Schering Res Found Workshop 2006:107–27.Google Scholar
  47. 47.
    Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol. 2005;5:521–31.CrossRefPubMedGoogle Scholar
  48. 48.
    Elloumi-Zghal H, Barbouche MR, Chemli J, Bejaoui M, Harbi A, Snoussi N, et al. Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille calmette-guerin infection. J Infect Dis. 2002;185:1468–75.CrossRefPubMedGoogle Scholar
  49. 49.
    Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H. Missense mutation of the interleukin-12 receptor beta1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood. 2001;97:2688–94.CrossRefPubMedGoogle Scholar
  50. 50.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8:967–74.CrossRefPubMedGoogle Scholar
  52. 52.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.CrossRefPubMedGoogle Scholar
  53. 53.
    Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis. 2006;12:9–15.CrossRefPubMedGoogle Scholar
  54. 54.
    Umetsu DT, DeKruyff RH. Th1 and Th2 CD4+ cells in the pathogenesis of allergic diseases. Proc Soc Exp Biol Med. 1997;215:11–20.PubMedGoogle Scholar
  55. 55.
    Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–33.CrossRefPubMedGoogle Scholar
  56. 56.
    Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129:550–64.PubMedGoogle Scholar
  57. 57.
    Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMedGoogle Scholar
  58. 58.
    Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–61.CrossRefPubMedGoogle Scholar
  59. 59.
    Denning TL, Qi H, Konig R, Scott KG, Naganuma M, Ernst PB. CD4+ Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions between CD4 and class II MHC. J Immunol. 2003;171:2279–86.PubMedGoogle Scholar
  60. 60.
    Hosoe N, Miura S, Watanabe C, Tsuzuki Y, Hokari R, Oyama T, et al. Demonstration of functional role of TECK/CCL25 in T lymphocyte–endothelium interaction in inflamed and uninflamed intestinal mucosa. Am J Physiol Gastrointest Liver Physiol. 2004;286:G458–66.CrossRefPubMedGoogle Scholar
  61. 61.
    Lu B, Humbles A, Bota D, Gerard C, Moser B, Soler D, et al. Structure and function of the murine chemokine receptor CXCR3. Eur J Immunol. 1999;29:3804–12.CrossRefPubMedGoogle Scholar
  62. 62.
    Neurath MF, Finotto S, Fuss I, Boirivant M, Galle PR, Strober W. Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol. 2001;22:21–6.CrossRefPubMedGoogle Scholar
  63. 63.
    Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348:24–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Stephens GL, Shevach EM. Foxp3+ regulatory T cells: selfishness under scrutiny. Immunity. 2007;27:417–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007;8:457–62.CrossRefPubMedGoogle Scholar
  66. 66.
    Cong Y, Weaver CT, Lazenby A, Elson CO. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol. 2002;169:6112–9.PubMedGoogle Scholar
  67. 67.
    Rennick DM, Fort MM, Davidson NJ. Studies with IL-10-/- mice: an overview. J Leukoc Biol. 1997;61:389–96.PubMedGoogle Scholar
  68. 68.
    Coffman RL, Lebman DA, Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989;170:1039–44.CrossRefPubMedGoogle Scholar
  69. 69.
    Ruemmele FM, Brousse N, Goulet O. Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol. 2004;20:587–91.CrossRefPubMedGoogle Scholar
  70. 70.
    Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res. 2007;38:112–21.CrossRefPubMedGoogle Scholar
  71. 71.
    Allez M, Brimnes J, Dotan I, Mayer L. Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells. Gastroenterology. 2002;123:1516–26.CrossRefPubMedGoogle Scholar
  72. 72.
    Kraus TA, Toy L, Chan L, Childs J, Cheifetz A, Mayer L. Failure to induce oral tolerance in Crohn’s and ulcerative colitis patients: possible genetic risk. Ann N Y Acad Sci. 2004;1029:225–38.CrossRefPubMedGoogle Scholar
  73. 73.
    Kraus TA, Toy L, Chan L, Childs J, Mayer L. Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease. Gastroenterology. 2004;126:1771–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  1. 1.Immunology InstituteMount Sinai Medical CenterNew YorkUSA

Personalised recommendations