Skip to main content
SpringerLink
Log in

The Th1, Th2, and Th17 Paradigm in Inflammatory Bowel Disease

  • Chapter
  • First Online:
Book cover Crohn's Disease and Ulcerative Colitis

Abstract

Effectiveness of monoclonal antibody against TNF-α as a treatment for both Crohn’s disease (CD) and ulcerative colitis (UC) changed the natural history of inflammatory bowel disease (IBD), and this subsequently encouraged many scientists to develop more effective therapies targeting other cytokine pathways. CD4+ T cells play central roles for the formation of cytokine networks in the pathogenesis of IBD. When CD4+ T cells are developed in the thymus and migrate to the peripheral tissues, they are called naïve T cells, which secrete little cytokines and cannot exert efficient effector function. When antigens specific for their own T-cell receptors (TCR) are presented to naïve T cells by antigen-presenting cells (APC) through MHC class-II/TCR signals with co-stimulatory signals, naïve T cells differentiate to helper T cells, which secrete characteristic types of cytokines and express specific transcription factors. Cytokines in the environment where antigen presentation occurs determine the polarization of these helper T (Th) cell subgroups. Classic helper T cells have been classified as Th1 or Th2. Th17, which is a novel subset of effector T cells, and regulatory T cells (Treg), which regulate effector T cells negatively, have taken part in them recently. In the past, CD was thought to be Th1-mediated disease, while UC was thought to be Th2-mediated disease. However, recently, it has been reported that Th17 are deeply involved in the pathogenesis of multiple animal models of IBD that were thought to be Th1 or Th2 models, and actually Th17 cytokines are highly expressed in the intestinal mucosa of both CD and UC patients. In addition, according to the results of GWAS (Genome Wide Association Study), there are highly significant associations between genomic regions of Th17/IL-23 pathway and IBD. This section will be helpful for the understanding of future immunologic therapies for IBD, which seems to become more and more complex.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 249.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78. Review.

    Article  PubMed  CAS  Google Scholar 

  2. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9(6):641–9.

    Article  PubMed  CAS  Google Scholar 

  3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541–9.

    Article  PubMed  CAS  Google Scholar 

  4. Zenewicz LA, Antov A, Flavell RA. CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol Med. 2009;15(5):199–207. Review.

    Article  PubMed  CAS  Google Scholar 

  5. Maynard CL, Weaver CT. Intestinal effector T cells in health and disease. Immunity. 2009;31(3):389–400. Review.

    Article  PubMed  CAS  Google Scholar 

  6. 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. Review.

    Article  PubMed  CAS  Google Scholar 

  7. Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28(1):29–39.

    Article  PubMed  CAS  Google Scholar 

  8. Abraham C, Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2009;60:97–110. Review.

    Article  PubMed  CAS  Google Scholar 

  9. Atarashi K, Nishimura J, Shima T, et al. ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008;455(7214):808–12.

    Article  PubMed  CAS  Google Scholar 

  10. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87. Review.

    Article  PubMed  CAS  Google Scholar 

  11. Neurath MF, Weigmann B, Finotto S, et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J Exp Med. 2002;195(9):1129–43.

    Article  PubMed  CAS  Google Scholar 

  12. Simpson SJ, Shah S, Comiskey M, et al. T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells. J Exp Med. 1998;187(8):1225–34.

    Article  PubMed  CAS  Google Scholar 

  13. Berg DJ, Davidson N, Kühn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996;98(4):1010–20.

    Article  PubMed  CAS  Google Scholar 

  14. Powrie F, Leach MW, Mauze S, et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994;1(7):553–62.

    Article  PubMed  CAS  Google Scholar 

  15. Kullberg MC, Rothfuchs AG, Jankovic D, et al. Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun. 2001;69(7):4232–41.

    Article  PubMed  CAS  Google Scholar 

  16. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495–549. Review.

    Article  PubMed  CAS  Google Scholar 

  17. Boirivant M, Fuss IJ, Chu A, Strober W. Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med. 1998;188(10):1929–39.

    Article  PubMed  CAS  Google Scholar 

  18. Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182(5):1281–90.

    Article  PubMed  CAS  Google Scholar 

  19. Heller F, Fuss IJ, Nieuwenhuis EE, et al. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17(5):629–38.

    Article  PubMed  CAS  Google Scholar 

  20. Fuss IJ, Neurath M, Boirivant M, 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(3):1261–70.

    PubMed  CAS  Google Scholar 

  21. Monteleone G, Biancone L, Marasco R, et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997;112(4):1169–78.

    Article  PubMed  CAS  Google Scholar 

  22. Okazawa A, Kanai T, Watanabe M, et al. Th1-mediated intestinal inflammation in Crohn’s disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement. Am J Gastroenterol. 2002;97(12):3108–17.

    Article  PubMed  CAS  Google Scholar 

  23. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004;351(20):2069–79.

    Article  PubMed  CAS  Google Scholar 

  24. Fuss IJ, Heller F, Boirivant M, 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(10):1490–7.

    PubMed  CAS  Google Scholar 

  25. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–3.

    Article  PubMed  CAS  Google Scholar 

  26. Izcue A, Hue S, Buonocore S, et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity. 2008;28(4):559–70.

    Article  PubMed  CAS  Google Scholar 

  27. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116(5):1310–6.

    Article  PubMed  CAS  Google Scholar 

  28. Wiekowski MT, Leach MW, Evans EW, et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol. 2001;166(12):7563–70.

    PubMed  CAS  Google Scholar 

  29. Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132(7):2359–70.

    Article  PubMed  CAS  Google Scholar 

  30. Ogawa A, Andoh A, Araki Y, et al. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol. 2004;110(1):55–62.

    Article  PubMed  CAS  Google Scholar 

  31. Yang XO, Chang SH, Park H, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063–75.

    Article  PubMed  CAS  Google Scholar 

  32. Awasthi A, Kuchroo VK. IL-17A directly inhibits TH1 cells and thereby suppresses development of intestinal inflammation. Nat Immunol. 2009;10(6):568–70.

    Article  PubMed  CAS  Google Scholar 

  33. Fina D, Sarra M, Fantini MC, et al. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008;134(4):1038–48.

    Article  PubMed  CAS  Google Scholar 

  34. Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947–57.

    Article  PubMed  CAS  Google Scholar 

  35. Luci C, Reynders A, Ivanov II, et al. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol. 2009;10(1):75–82.

    Article  PubMed  CAS  Google Scholar 

  36. Mudter J, Amoussina L, Schenk M, et al. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Invest. 2008;118(7):2415–26.

    PubMed  CAS  Google Scholar 

  37. Abraham C, Cho J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(7):1090–100. Review.

    Article  PubMed  Google Scholar 

  38. Kamada N, Hisamatsu T, Okamoto S, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008;118(6):2269–80.

    PubMed  CAS  Google Scholar 

  39. Fuss IJ, Becker C, Yang Z, 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(1):9–15.

    Article  PubMed  Google Scholar 

  40. Maul J, Loddenkemper C, Mundt P, et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128(7):1868–78.

    Article  PubMed  CAS  Google Scholar 

  41. Himmel ME, Hardenberg G, Piccirillo CA, et al. The role of T-regulatory cells and Toll-like receptors in the pathogenesis of human inflammatory bowel disease. Immunology. 2008;125(2):145–53. Review.

    Article  PubMed  CAS  Google Scholar 

  42. Makita S, Kanai T, Oshima S, et al. CD4  +  CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol. 2004;173(5):3119–30.

    PubMed  CAS  Google Scholar 

  43. Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40(11):1319–23.

    Article  PubMed  CAS  Google Scholar 

  44. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033–45.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Yasuhiro Nemoto MD, PhD & Mamoru Watanabe MD, PhD

Authors
  1. Yasuhiro Nemoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mamoru Watanabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mamoru Watanabe MD, PhD .

Editor information

Editors and Affiliations

  1. Medical School of the Humboldt Universit, Department of Medicine, Charité Medical Center, Virchow Hospita, Berlin, 13344, Germany

    Daniel C. Baumgart

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Nemoto, Y., Watanabe, M. (2012). The Th1, Th2, and Th17 Paradigm in Inflammatory Bowel Disease. In: Baumgart, D. (eds) Crohn's Disease and Ulcerative Colitis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0998-4_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-0998-4_15

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4614-0997-7

  • Online ISBN: 978-1-4614-0998-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation