Pathophysiology

In Crohn's disease, the uncontrolled inflammatory response to antigens in the gut is partly a result of an immune system dysfunction. There is an imbalance in the local mucosal production of pro-inflammatory cytokines (INF-γ) over anti-inflammatory cytokines (1). These pro-inflammatory cytokines are important mediators of tissue damage in Crohn's disease (1).

Excessive CD4+ T cell activation is crucial in the pathogenesis of tissue damage in Crohn's disease (1). The T helper 1 cells (TH1), an aggressive form of T cells, mediate this inflammatory response (1, 2). An overproduction of IL-12, which is a macrophage-derived cytokine, creates a TH1 response resulting in an exaggerated production of pro-inflammatory cytokines (2).

Among the pro-inflammatory cytokines, TNF-α plays a key role in inflammatory processes associated with Crohn's disease (1). TNF-α activates macrophages, promotes the release of other pro-inflammatory cytokines and mediators (nitric oxide, prostacyclin, platelet-activating factor), and promotes the recruitment of new inflammatory cells into the mucosa by inducing the expression of adhesion molecules on vascular endothelium (1).

The damage caused by chronic inflammation in the bowel, due in part to the action of pro-inflammatory cytokines, manifests as thickening of the bowel wall and narrowing of the lumen (3, 4). As the disease advances, these events may eventually lead to strictures, obstruction, fistulization, abscess formation, adhesions, and malabsorption, which are complications characteristic of Crohn's disease (3, 4).

Glossary

Abscess Formation

A walled-off pocket of infection that is generally associated with an ulcer or fistula. Patients with an abscess will have increased abdominal pain and may experience bouts of fever (5, 6).

Adhesions

An adhesion is a band of scar tissue that binds together two anatomic surfaces, which are normally separated from each other and occur as a result of inflammation or surgery (7).

Illustration 1 : Adhesions
adhesions
University of Maryland Medical Center. Inflammatory Bowel Disease Program. Adhesion. Available at: http://www.umm.edu/imagepages/17118.htm. Accessed August 14, 2006.

CD4+ T cell

T cell with CD4 receptor on its surface that recognizes foreign antigens and secretes cytokines that stimulate B cells and T cells (8).

Cytokines

A collective term for a diverse group of soluble glycoproteins released by cells of the immune system that are active at low concentrations and bind to specific receptors to produce autocrine, paracrine, and endocrine effects (9,10).

Fistulization

Fistulas are channels of infection resulting from ulcerations in the lining of the intestine. These channels may continue until they reach the surface of an organ. A fistula may connect two adjacent loops of intestine or may connect the intestine to the bladder, vagina, skin, or other organ (11, 12).

Illustration 2 : Fistulization

University of Maryland Medical Center. Inflammatory Bowel Disease Program. Crohn's Disease. Avaliable at: http://www.umm.edu/imagepages/19291.htm. Accessed August 14, 2006.

IL

Interleukin; A general term for a group of multifunctional cytokines that are produced by a variety of lymphoid and nonlymphoid cells and whose effects occur at least partly within the lymphopoietic system (13).

INF-γ

Interferon-gamma is a dimerized soluble cytokine which is a Type II Interferon. In contrast to interferon-α and interferon-β which can be expressed by all cells, IFN-γ is secreted by T lymphocytes and NK cells only (14).

Intestinal Bowel Obstruction

A partial or complete blockage of the bowel that results in the failure of the intestinal contents to pass through (15).

Illustration 3 : Intestinal Bowel Obstruction
xray
University of Maryland Medical Center. Inflammatory Bowel Disease Program. Intestinal Obstruction. Available at: http://www.umm.edu/imagepages/3069.htm. Accessed August 14, 2006.

Intestinal Strictures

Narrowing of the intestine, typically short (2 to 3 cm in length).. Patients with extensive disease and continuous symptoms without remission often develop strictures. Strictures tend to occur approximately 5-25 years after disease onset (16).

TNF-α

Tumor necrosis factor α; a pro-inflammatory cytokine produced by activated macrophages and T cells among other cells. TNF induces other pro-inflammatory cytokines and activates leucocytes and induces acute phase reactions and metalloproteinases (17).


References

  1. Pallone F, Monteleone G, Monteleone I, Biancone L. The immune system in inflammatory bowel disease. In Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. London: Churchill Livingstone. Elsevier Limited, 2003: 85-93.
  2. Hanauer SB. Inflammatory Bowel Disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006; 12 (Suppl 1): S3-S9.
  3. Gopal L, Nachimuthu S. Crohn Disease. eMedicine from WebMD. Available at: http://www.emedicine.com/MED/topic477.htm. Accessed June 23, 2006. Last updated May 23, 2006.
  4. Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Harrison's Internal Medicine. McGraw-Hill Access Medicine. 2006. The McGraw-Hill Companies. Available at: http://www.accessmedicine.com/content.aspx?aID=90323.
  5. Jones OM. McC.Mortensen NJ. Surgical treatment of Crohn's disease. In Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. London: Churchill Livingstone. Elsevier Limited, 2003: 513-538.
  6. Crohn's Disease. Health A to Z, Your Family Health Site. 1999-2006 Medical Network Inc. Available at: http://www.healthatoz.com/healthatoz/Atoz/ency/crohns_disease.jsp.
  7. University of Maryland Medical Center. Available at: http://www.umm.edu/ency/article/001493.htm.
  8. Definition of T-4 Cell. MedicineNet.com. 196-2006 MedicineNet Inc. Available at: http://www.medterms.com/script/main/art.asp?articlekey=11301.
  9. Fein AM. Abraham EM. Can we make sense out of cytokines? Chest 2000;117:932-934.
  10. HON Dossier. Health on the Net Foundation. Available at: http://www.hon.ch/Library/Theme/Allergy/Glossary/cytokine.html.
  11. University of Maryland Medical Center. Available at: http://www.umm.edu/imagepages/19291.htm.
  12. Surgery for Crohn's Disease. Crohn's and Colitis Foundation of America. Available at: http://www.ccfa.org/info/surgery/surgerycd.
  13. Dorland's Illustrated Medical Dictionary. Edition 28. WB Saunders Co; Philadelphia, PA: 1994.
  14. Answers.com. Available at: http://www.answers.com/topic/interferon-gamma.
  15. University of Maryland Medical Center. Available at: http://www.umm.edu/ency/article/000260.htm.
  16. Ulcerative Colitis. IBD Answers. Available at: http://www.ibdanswers.com/UlcerativeColitisAndNutrition.
  17. Rutgeerts P, van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 2004;126:1593-1610.
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