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Inflammatory Bowel Disease Learning Zone

Immunology of IBD

Read time: 10 mins
Last updated:14th Oct 2021
Published:14th Oct 2021

Get to grips with the immunological aspects of inflammatory bowel disease.

  • Visualise the role of innate/adaptive immunity with our diagrammatic summary
  • Improve your knowledge of how lymphocyte trafficking is altered in IBD
  • Learn how IBD pathophysiology has informed recent drug development

Maintaining intestinal homeostasis

The gut mucosal immune system forms a protective barrier that preserves the integrity of the gastrointestinal tract1.

The gastrointestinal tract represents the largest area of contact with the external environment in the human body2. In healthy individuals, intestinal homeostasis is maintained through constant interaction between the contents of the gastrointestinal tract and the gut mucosal immune system1. This involves striking a balance between tolerance to food, self- and non-pathogenic microbial antigens, and protection against invading pathogens3.

Innate and adaptive immunity in IBD

In genetically predisposed individuals, IBD may develop as the result of a dysregulated immune response against a microbiome that exists in a state of dysbiosis4. It is thought that both innate and adaptive immune pathways play a role in producing the excessive intestinal inflammatory response that characterises patients with IBD (Figure 1)5. Crosstalk between the two is controlled by dendritic cells and is crucial for the maintenance of intestinal homeostasis3.

While pro-inflammatory cytokines produced by certain T cell subsets are associated with inflammation and tissue damage in inflammatory bowel disease, some T cells may also produce anti-inflammatory cytokines that are thought to aid barrier function and resolution of inflammation6.

T3 IBD - Jan2021.Fig1.png

Figure 1. Innate and adaptive immune cell activation in IBD. Innate and adaptive immune cells involved in the pathogenesis of IBD and cytokines released by the different cell subsets in the affected tissue are shown (Adapted6). CD, Crohn’s disease; IFN-γ, interferon-γ; IL, interleukin; ILC, innate lymphoid cells; NK, natural killer; TNF, tumour necrosis factor; TGF, transforming growth factor; UC, ulcerative colitis.

Lymphocyte homing in IBD

Infiltration of the intestinal mucosa by large numbers of T lymphocytes is a key feature of IBD3. Naïve T-lymphocytes are activated in the gut-associated lymphoid organs via interaction with antigen-loaded dendritic cells. T lymphocytes activated in the gut lymphoid organs gain gut-specific homing receptors enabling them to home back to the gut and enter the lamina propria through tissue-specific homing pathways6–9. Here, T lymphocytes can differentiate into other cell types capable of damaging the gut tissue6,7

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is expressed on the surface of intestinal endothelial cells and in gut-associated lymphoid tissues10. Lymphocytes bearing the α4β7 integrin selectively bind to MAdCAM-1, facilitating migration of these lymphocytes to the gut11. Expression of MAdCAM-1 is increased in the inflamed tissue of patients with IBD via the activity of pro-inflammatory cytokines10,11.

Both inflammatory cytokines and T lymphocytes and their derivatives cause destruction of epithelial cells and damage the gut wall. This allows an increased number of microbes to breach the epithelial barrier6,12,13.

Production of inflammatory cytokines by activated immune cells located in the intestinal tissues results in recruitment of further immune cells, which in turn produce more cytokines, leading to anti-epithelial cytotoxicity favouring further translocation of luminal antigens, which perpetuates a cycle of inflammation in the gut5,7. Sustained intestinal inflammation results in structural and functional bowel abnormalities with associated disability7,14.

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References

  1. Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res. 2017;4:14.
  2. Dave M, Papadakis KA, Faubion Jr WA. Immunology of inflammatory bowel disease and molecular targets for biologics. Gastroenterol Clin North Am. 2014;43(3):405–424.
  3. Ahluwalia B, Moraes L, Magnusson MK, Öhman L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol. 2018;53(4):379–389.
  4. Kok K, Ibarra A, Lindsay J. New Therapeutic Strategies. In: Sturm A, White L, editors. Inflammatory Bowel Disease Nursing Manual. 2019. Switzerland AG. Springer Nature: 99–112.
  5. Silva FAR, Rodrigues BL, de Lourdes S Ayrizono M, Leal RF. The Immunological Basis of Inflammatory Bowel Disease. Gastroenterol Res Pract. 2016;2097274.
  6. Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019;20(8):970–979.
  7. Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: Mechanistic insights and therapeutic advances. Gut. 2019;68(9):1688–1700.
  8. Carman C V., Martinelli R. T lymphocyte-endothelial interactions: Emerging understanding of trafficking and antigen-specific immunity. Front Immunol. 2015;6:603.
  9. Kogan AN, von Andrian UH. Lymphocyte Trafficking. In: Tuma RF, Durán WN, Ley K, editors. Microcirculation. 2008. San Diego: 449–482.
  10. Duijvestein M, D’Haens GR. Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD. Exp Opin Biol Ther. 2019;19(4):361–366.
  11. Bravatà I, Allocca M, Fiorino G, Danese S. Integrins and adhesion molecules as targets to treat inflammatory bowel disease. Curr Opin Pharmacol. 2015;25:67–71.
  12. Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its role in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14(9):1298–1312.
  13. Arseneau KO, Cominelli F. Targeting leukocyte trafficking for the treatment of inflammatory bowel disease. Clin Pharmacol Ther. 2015;97(1):22–28.
  14. Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17(6):1415–1422.
  15. Duijvestein M, Battat R, Vande Casteele N, D’Haens GR, Sandborn WJ, Khanna R, et al. Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2018;16(1):129–146.
  16. Chudy-Onwugaje KO, Christian KE, Farraye FA, Cross RK. A State-of-the-Art Review of New and Emerging Therapies for the Treatment of IBD. Inflamm Bowel Dis. 2019;25(5):820–830.
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