Pathogenesis of Crohns Disease

Although significant advances in understanding the pathogenesis of CD have been made, there are many unknowns. CD is believed to be caused by a combination of genetic and environmental factors, affecting the mucosal immune system and culminating in an aberrant inflammatory response (Korzenik and Podolsky 2006) (Fig. 12.3). It is a polygenic disease with probable genetic heterogeneity. Some genes are associated with the disease itself, whereas others increase the risk of the disease or are associated with the location or behavior of the disease (Lakatos et al. 2006). Caspase recruitment domain family member 15 (CARD15, also known as IBD1 or NOD2) was the first specific gene associated with inflammatory bowel disease (IBD) and is believed to confer the critical mutation on chromosome 16

Normal

Crohn's Disease

"cobble-stoning"

fat-wrapping

Gastroduodenal

Gastroduodenal

Colon alone 20%

Normal

Crohn's Disease

"cobble-stoning"

fat-wrapping

Crohn Disease

Fig. 12.1. a Anatomic distribution of Crohn's disease. b Comparison ofthe appearance of normal and Crohn's mucosa: gross (top); histologic (center); endoscopic (bottom). (Reprinted with permission from Bayless et al. 2006)

Fig. 12.2. Treatment algorithm of therapeutic options for Crohn's disease. 5-ASA 5-aminosalicylate, IL interleukin, IV intravenous. (Reprinted with permission from Bayless et al. 2006)

(Hugot et al. 2001; Ogura et al. 2001). CARD15 is the intracellular receptor for peptidoglycan-derived mura-myl dipeptide and is involved in cell activation via NFkB. CARD15 mutations are associated with diminished mucosal alpha-defensin expression, which could be the cause of decreased innate immune response to endogenous bacteria (Kobayashi et al. 2005; Wehkamp et al. 2004). Moreover, in healthy first-degree relatives of patients with CD, high mucosal permeability was associated with the presence of CARD15 mutation, indicating that genetic factors may be involved in the impairment of the intestinal barrier function in families with IBD (Buhner et al. 2006). Organic cation transporter 1 (also known as IBD5) also has been associated with CD, especially fistulizing disease. Mutations in this gene affect the ability of transporters to pump xenobi-

Fig. 12.3. Immunopathogenesis of Crohn's disease. (Reprinted with permission from Bayless et al. 2006)

Fig. 12.4. Novel therapeutic targets in inflammatory bowel disease (IBD). Potential therapies in IBD encompass interventions targeting a variety of pathways in the inflammatory cascade. These include altering luminal factors, enhancing intestinal repair, augmenting the intestinal innate immune barrier function, inhibiting cell adhesion, and blocking cytokine activity. GM-CSF granu-locyte-macrophage colony-stimulating factor, ICAM-1 intercellular adhesion molecule 1, IFN interferon, IL interleukin, M macrophage cell, PMN peripheral mono-nuclear cell, SAM selective adhesion molecule, TNF tumor necrosis factor. (Reprinted with permission from Korzenik and Podolsky 2006)

Fig. 12.3. Immunopathogenesis of Crohn's disease. (Reprinted with permission from Bayless et al. 2006)

otics and amino acids across cell membranes (Pelteko-va et al. 2004). Drosophila Discs Large Homolog 5 (DLG5), located on chromosome 10q23, has been associated with IBD in the German population. This mutation is thought to impair the ability of DLG5 to function as a guanylate kinase and to maintain epithelial polarity, affecting epithelial permeability (Stoll et al. 2004). Other genes and loci are currently under investigation in CD (Noble et al. 2006). These investigations, in addition to aiding the understanding of the pathophysiolo-gy of the disease, may give way not only to potential screening and prevention programs targeted at specific genotypes, but also to future gene therapies for CD (Baert et al. 2004; Schreiber 2006).

In patients with CD, the mucosal immune system may be more exposed to potentially harmful pathogens and foreign antigens, resulting in the production of inflammatory cytokines and T-cell differentiation. The mucosal inflammation of established CD is dominated by CD4-positive T lymphocytes with a type 1 helper phenotype, characterized by the production of interferon-y (IFN-y) and tumor necrosis factor (TNF). Other components of the intestinal matrix, such as adhe sion molecules, matrix metalloproteinases, intestinal epithelial cells, fibroblasts, and granulocytes, interact in a complex network that balances inflammation and healing (Baert et al. 2004).

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