Skip to main content
SpringerLink
Log in

Role of the innate immune system in the development of chronic colitis

  • Positioning of treatment for IBD by repairing mucosa
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Based on Pasteur’s work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gutassociated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tlaskalova H, Sterzl J, Hajek P, Pospisol M, Riha I, Marvanova H, et al. The development of antibody formation during embryonal and postnatal periods. In: Sterzl J, Riha I, editors. Development aspects of antibody formation and structure. Prague: Academic Publishing House; 1970. p. 767–90.

    Google Scholar 

  2. Carter PB, Pollard M. Host responses to “normal” microbial flora in germ-free mice. J Reticuloendothelial Soc 1971;9:580–7.

    CAS  Google Scholar 

  3. Berg RD, Savage DC. Immune responses of specific pathogen-free and gnotobiotic mice to antigens of indigenous and nonindigenous microorganisms. Infect Immun 1975;11:320–9.

    PubMed  CAS  Google Scholar 

  4. Shroff KE, Meslin K, Cebra JJ. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun 1995;63:3904–13.

    PubMed  CAS  Google Scholar 

  5. Cebra JJ, Jiang HQ, Sterzl J, Tlasklova-Hogenova H. The role of mucosal microbiota in the development and maintenance of the mucosal immune system. In: Ogra PL, Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, editors. Mucosal immunology. San Diego: Academic; 1999. p. 266–80.

    Google Scholar 

  6. De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 1994;264: 703–7.

    Article  PubMed  Google Scholar 

  7. Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, Kuklin NA, et al. Lymphotoxin-a-deficient mice: effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol 1995; 155:1685–93.

    PubMed  CAS  Google Scholar 

  8. Alimzhanov MB, Kuprashi DV, Kosco-Vibois MH, Luz A, Turetskaya RL, Tarakhovsky A, et al. Abnormal development of secondary lymphoid tissues in lymphotoxin b-deficient mice. Proc Natl Acad Sci USA 1997;94:9302–7.

    Article  PubMed  CAS  Google Scholar 

  9. Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, et al. Lymphotoxin-b, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 1993;72:847–56.

    Article  PubMed  CAS  Google Scholar 

  10. Glimcher LH. Lineage commitment in lymphocytes: controlling the immune response. J Clin Invest 2001;108:25–30.

    Google Scholar 

  11. Guy-Grand D, Griscelli C, Vassalli F. Peyer’s patches, gut IgA plasma cells and thymic function: study in nude mice bearing thymic grafts. J Immunol 1975;115:361–4.

    PubMed  CAS  Google Scholar 

  12. Craig SW, Cebra JJ. Peyer’s patches: an enriched source of precursors for IgA-producing immunocytes in the rabbit. J Exp Med 1971;134:188–200.

    Article  PubMed  CAS  Google Scholar 

  13. Elson CO, Heck JA, Strober W. T-cell regulation of murine IgA synthesis. J Exp Med 1979;149:632–43.

    Article  PubMed  CAS  Google Scholar 

  14. Schultz CL, Coffman RL. Control of isotype switching by T cells and cytokines. Curr Opin Immunol 1991;3:350–4.

    Article  PubMed  CAS  Google Scholar 

  15. Coffman RL, Lebman DA, Shrader B. Transforming growth factor b specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 1989;170:1039–44.

    Article  PubMed  CAS  Google Scholar 

  16. Dubois B, Bridon JM, Fayette J, Barthelemy C, Banchereau J, Caux C, et al. Dendritic cells directly modulate B cell growth and differentiation. J Leukocyte Biol 1999;66:224–30.

    PubMed  CAS  Google Scholar 

  17. Weiner HL. Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 1997;18:335–43.

    Article  PubMed  CAS  Google Scholar 

  18. Strobel S, Mowat AM. Immune responses to dietary antigens: oral tolerance. Immunol Today 1998;19:173–81.

    Article  PubMed  CAS  Google Scholar 

  19. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675–80.

    Article  PubMed  CAS  Google Scholar 

  20. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–83.

    Article  PubMed  CAS  Google Scholar 

  21. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394–7.

    Article  PubMed  CAS  Google Scholar 

  22. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. A family of human receptors structurally related to Drodophila Toll. Proc Natl Acad Sci USA 1998;95:588–93.

    Article  PubMed  CAS  Google Scholar 

  23. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J Biol Chem 1999;274:17406–9.

    Article  PubMed  CAS  Google Scholar 

  24. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda K, et al. Cutting edge. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749–52.

    PubMed  CAS  Google Scholar 

  25. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. Toll-like receptor recognizes bacterial DNA. Nature2000;408: 740–5.

    Article  PubMed  CAS  Google Scholar 

  26. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor-5. Nature 2001;410:1099–103.

    Article  PubMed  CAS  Google Scholar 

  27. Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002;168:554–61.

    PubMed  CAS  Google Scholar 

  28. Kaisho T, Akira S. Dendritic-cell function in Toll-like receptor-and MyD88-knockout mice. Trends Immunol 2001;22:78–83.

    Article  PubMed  CAS  Google Scholar 

  29. Adachi O, Kawai T, Takeda K, Tsutsui H, Sakagami M, Nakanishi K, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998;9: 143–50.

    Article  PubMed  CAS  Google Scholar 

  30. MacDonald TT, Monteleone G. IL-12 and Thl immune responses in human Peyer’s patches. Trends Immunol 2001;22:244–7.

    Article  PubMed  CAS  Google Scholar 

  31. Nagata S, McKenzie C, Pender SLF, Bajaj-Elliott M, Fairclough PD, Walker-Smith JA, et al. Human Peyer’s patch T cells are sensitized to dietary antigen and display a Th cell type 1 cytokine profile. J Immunol 2000;165:5315–21.

    PubMed  CAS  Google Scholar 

  32. Yoshida H, Honda K, Shinkura R, Adachi S, Nishikawa S, Maki K, et al. IL-7 receptor α+ CD3- cells in the embryonic intestine induces the organizing center of Peyer’s patches. Int Immunol 1999;11:643–55.

    Article  PubMed  CAS  Google Scholar 

  33. Simon GL, Gorbach SL. Intestinal flora in health and disease. Gastroenterology 1984;86:174–93.

    PubMed  CAS  Google Scholar 

  34. Duchmann R, Neurath MF, Meyer zum Buschenfelde KH. Responses to self and non-self intestinal microflora in health and inflammatory bowel disease. Res Immunol 1997;148:589–94.

    Article  PubMed  CAS  Google Scholar 

  35. Lebman DA, Edmiston JS. The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes. Microbes Infect 1999;l:1297–304.

    Article  Google Scholar 

  36. Ehrhardt RO, Ludviksson BR, Gray B, Neurath M, Strober W. Induction and prevention of colonic inflammation in IL-2-deficient mice. J Immunol 1997;158:566–73.

    PubMed  CAS  Google Scholar 

  37. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993;75:263–74.

    Article  PubMed  CAS  Google Scholar 

  38. Duchmann R, Schmitt E, Knolle P, Meyer zum Buschenfelde KH, Neurath M. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol 1996;26:934–8.

    Article  PubMed  CAS  Google Scholar 

  39. Mombaerts P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 1993;75:275–82.

    Article  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. Duchmann R, May E, Heike M, Knolle P, Neurath M, Meyer zum Buschenfelde KH. T cell specificity and cross reactivity towards enterobacteria, Bacteroides, Bifidobacterium, and antigens from resident intestinal flora in humans. Gut 1999;44:812–8.

    Article  PubMed  CAS  Google Scholar 

  42. Macpherson A, Khoo UY, Forgacs I, Philport-Howard J, Bjarnason I. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 1996;38:365–75.

    Article  PubMed  CAS  Google Scholar 

  43. Hollander D. Permeability in Crohn’s disease: altered barrier function in healthy relatives? Gastroenterology 1993; 104:1848–51.

    PubMed  CAS  Google Scholar 

  44. Satsangi J, Jewell DP, Rosenberg WM, Bell JI. Genetics of inflammatory bowel disease. Gut 1994;35:696–700.

    Article  PubMed  CAS  Google Scholar 

  45. Podolsky DK. Inflammatory bowel disease (first of two). N Engl J Med 1995;325:928–37.

    Article  Google Scholar 

  46. Fiocchi C. Inflammatory bowel disease—etiology and pathogenesis. Gastroenterology 1998;115:182–205.

    Article  PubMed  CAS  Google Scholar 

  47. Fuss IJ, Neurath M, Boirvant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996;157:1261–70.

    PubMed  CAS  Google Scholar 

  48. Parronchi P, Romagnani P, Annuziato F, Sampognaro S, Becchio A, Giannarini L, et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am J Pathol 1997;150:823–32.

    PubMed  CAS  Google Scholar 

  49. Kanai T, Watanabe M, Okazawa A, Sato T, Yamazaki M, Okamoto S, et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology 2001;121:875–88.

    Article  PubMed  CAS  Google Scholar 

  50. Lang KA, Peppercorn MA. Medical therapy for Crohn’s disease. In: Kirsner JB, editors. Inflammatory bowel disease. Philadelphia: W.B. Saunders; 2000. pp. 557–77.

    Google Scholar 

  51. Colombel JF, van Kruiningen HJ. Antibiotics in Crohn’s disease. Gut 2001;48:647–8.

    Article  PubMed  CAS  Google Scholar 

  52. Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:357–65.

    PubMed  CAS  Google Scholar 

  53. Prantera C, Zannoni F, Scribano ML, Berto E, Andredi A, Kohn A, et al. An antibiotics regimen for the treatment of active Crohn’s disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996;91:328–32.

    PubMed  CAS  Google Scholar 

  54. Colombel JF, Lemann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas JL, et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Am J Gastroenterol 1999;94:674–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Takanori Kanai, Ryoichi Iiyama, Takahiro Ishikura, Koji Uraushihara, Teruji Totsuka, Motomi Yamazaki, Tetsuya Nakamuma & Mamoru Watanabe

Authors
  1. Takanori Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryoichi Iiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahiro Ishikura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koji Uraushihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teruji Totsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Motomi Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tetsuya Nakamuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mamoru Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kanai, T., Iiyama, R., Ishikura, T. et al. Role of the innate immune system in the development of chronic colitis. J Gastroenterol 37 (Suppl 14), 38–42 (2002). https://doi.org/10.1007/BF03326411

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03326411

Keywords

Search

Navigation