Crohn's disease pathophysiology

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Crohn's disease
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Genetic and environmental factors play a key role in the pathogenesis of Crohn's disease. Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease and with susceptibility to certain phenotypes of disease location and activity. Environmental factors include autoimmune Disease and dysregulated Immune Response to Commensal Bacteria. Characteristic features of the pathology that point toward Crohn's disease are transmural pattern of inflammation and skip lesions. Under microscopy Granulomas are seen, which are aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.

Pathophysiology

The exact pathogenesis of Crohn's disease is not clearly understood. However, 4 components have been proved to play a key role in the pathogenesis of Crohn's disease.

• Genetic component
• Stress and environmental component
• Microbial component
• Inflammatory component

Genetic Component

Genes involved

• NOD2/CARD15 gene
• OCTN1 gene
• DLG5 gene
• TLR4 gene

Genes	Chromosome		Function	Mutation
NOD2/CARD15	16	16q12.1	Encodes a scaffolding protein important for maintaining epithelial integrity	Disrupts normal epithelial integrity
OCTN1	05	5q31	Ecodes an ion channel	Alters the function of cation transporters and cell-to-cell signaling
DLG5	10	10q22.3	Interact additively with the NOD2/CARD15 gene	Iincrease susceptibility to CD along with CARD15
TLR4	09	9q33.1	Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response	Altered immune response to pathogens and a subsequent increase in inflammation.

Stress and Environmental Component

• Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
• Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
• Stress increases gut permeability along with other factors which inlude
  • Corticotropin-releasing factor
  • Autonomic nervous system
  • Enteric nervous system

Microbial Component

The possible mechanisms for a bacterial etiology in the development of CD include:

• Initial immune response to a specific pathogen resulting in intestinal infection
• Alterations in normal bacterial flora of the intestinal tract
• Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
• Alterations to the intestinal immune response

Infectious Pathogens Implicated in Crohn’s Disease
Escherichia coli Listeria monocytogenes Yersinia enterocolitica Mycobacterium avium subspecies paratuberculosis Measles virus

Immune Component

• Altered immune response:
  • An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease.
  • The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
  • Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence.
  • Antigen persistance leads to antibodies production against all the normal gut flora.
  • Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
• Cytokine response:
  • The primary precipitating event in Crohn's disease is T-cell mediated immune response.
  • Activated T cells are responsible for the release of cytokines.
  • The production of inflammatory cytokines results in ulceration and increased intestinal permeability.
  • The characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
  • The early lesions of Crohn's disease are characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
  • Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma), TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18) consistent with an Th1 immune response.
  • Tumor necrosis factor appears to play a significant role in the pathogenesis of CD.
    • TNF-alpha induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
    • Neutralization of TNF resulted in significant decrease in inflammation.
    • TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.

Genetics

• Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease and with susceptibility to certain phenotypes of disease location and activity.
• In earlier studies, only two genes were linked to Crohn's, but scientists now believe there are over eight genes that show genetics play a crucial role in the disease.
• Abnormalities in the immune system have often been invoked as being causes of Crohn's disease.
• It has been hypothesized that Crohn's disease involves augmentation of the T_h1 of cytokine response in inflammation.
• The most recent gene to be implicated in Crohn's disease is ATG16L1, which may reduce the effectiveness of autophagy, and hinder the body's ability to attack invasive bacteria.

Environmental factors

Environmental factors include:

• Autoimmune disease
• Dysregulated immune response to commensal bacteria

Autoimmune disease

• Inflammatory response directed toward a self-antigen is believed to be responsible for development of Crohn's disease.
• Neutrophils are the main group of the cells that are targeted.
• Antineutrophil antibodies activate complement factors and localize on the luminal surface of the epithelium resulting in the destruction of intestinal tissue.

Immune reponse

• T-cell activation from chronic inflammation resulting in tissue injury is believed to the main reason in the pathogenesis of Crohn disease.
• After T cell activation by antigen presentation, unrestrained responses of type 1 T helper (Th1) cells predominate in Crohn disease as a consequence of defective regulation.
• Th1 cytokines such as interleukin (IL)-12 and TNF-α stimulate the inflammatory response.
• Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances, including arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine.

Gross Pathology

Characteristic features of Crohn's disease on gross pathology include:

• Creeping fat
• Thick/rubbery intestinal wall
• Strictures (string sign on barium enema)
• Skip areas
• Aphthous mucosal ulcers

Microscopic Pathology

On microscopic analysis of the affected colon may show mucosal inflammation. Histo-pathological finding include

• Transmural inflammation
• Lymphoid aggregates throughout the wall of the colon.
• Focal infiltration of neutrophils along with mononuclear cells, may infiltrate into the crypts leading to inflammation (crypititis) or abscess (crypt abscess).
• Non- caseating Granulomas (aggregates of macrophage derivatives) known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.
• Blunting of the intestinal villi
• Atypical branching of the crypts
• Paneth cell metaplasia

H and E section of colectomy showing transmural inflammation.
Source:By The original uploader was Samir at English Wikipedia [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons

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