Mechanisms of Disease: Pathogenesis of Crohn's Disease and Ulcerative Colitis

R Balfour Sartor

Disclosures

Nat Clin Pract Gastroenterol Hepatol. 2006;3(7):390-407. 

In This Article

Genetics

Advances have occurred in understanding the genetics of human IBD, from studies based on single nucleotide polymorphism (SNP) and candidate gene approaches, and from studies in mouse experimental colitis that used transgenic and deletion (knockout) techniques.[3,4] Work in these two independent systems has produced partially overlapping results, with several genes implicated in both IBD and experimental colitis ( Table 1 ). The common threads are that the implicated genes regulate several important biologic functions, including immunoregulation, mucosal barrier integrity and microbial clearance and/or homeostasis.

The CARD15 Gene

The first gene to be associated with Crohn's disease was CARD15 (caspase recruitment domain family member 15, formerly known as NOD2).[5,6] There are three mutations—causing amino-acid substitutions Arg702Trp and Gly908Arg and the frameshift 1007fs—found within the region of CARD15 that encodes a leucine-rich repeat, which is responsible for bacterial recognition. At least one of these mutations is present in 25–35% of Crohn's disease patients of European ancestry, but not in Asian or African American Crohn's disease patients.[3] Mutations in CARD15 are associated with distal ileal Crohn's disease in particular, and have been found in some patients with stricturing disease.

The leucine-rich repeat region of CARD15 binds muramyl dipeptide (MDP), which is the biologically active moiety of peptidoglycan, a ubiquitous cell-wall polymer found in almost all bacteria.[7] The binding of MDP by dimerized CARD15 activates nuclear factor (NF)κB, which forms part of a central signaling pathway that stimulates the transcription of multiple genes that encode both proinflammatory and protective molecules. The mutations causing Arg702Trp, Gly908Arg and 1007fs cause defective MDP binding, but studies report conflicting consequences of having such mutations.

Mutant CARD15 fails to clear Salmonella from epithelial cells,[8] and clearance of invasive bacteria is dependent on NFκB activation via the cell-death regulatory protein GRIM-19.[9] It is also possible that defective CARD15 results in increased luminal bacterial populations, particularly within the crypts. CARD15 is constitutively expressed in Paneth cells,[10] the source of secreted antimicrobial peptides such as the α-defensins. Targeted deletion of Card15 in mice decreases α-defensin production and enhances susceptibility to experimental Listeria monocytogenes infection after oral, but not systemic (intraperitoneal), challenge.[11] These results are consistent with the decrease in α-defensin production seen in Crohn's disease patients, particularly those with CARD15 mutations.[12] In addition, Paneth cells are selectively expressed in the ileum, perhaps accounting for the distal ileal involvement of Crohn's disease in patients with CARD15 mutations.

Finally, Strober and colleagues have attempted to reconcile the observed activation of NFκB in patients with active Crohn's disease, rather than decreased activity predicted by a loss-of-function mutation. Their investigations demonstrated that, in CARD15-defective cells, Toll-like receptor 2 (TLR2) was unable to downregulate NFκB activation.[13].

These abnormalities could result in defective downregulation of the innate immune response to bacterial adjuvant stimulation, ineffective clearance of intracellular bacterial infection and proliferation of both luminal and mucosally adherent commensal bacteria. Each of these situations has been documented in Crohn's disease patients.[14]

SLC22A4 and SLC22A5

Two functional variants of the organic cation transporters OCTN1 and OCTN2 have been associated with Crohn's disease in association with CARD15 mutations.[15] Mutations in the transcribed region of SLC22A4, which encodes OCTN1, and the promoter region of SLC22A5, which encodes OCTN2, affect the transcription and function of these carnitine and organic cation transporters. These variants are most actively expressed in the intestinal epithelium, macrophages and T cells, and cause decreased carnitine transport. Although many studies have associated the region of chromosome 5 that contains SLC22A4 and SLC22A5 with Crohn's disease, some investigators are hesitant to identify the mutations in these genes as causative of Crohn's disease because of the tight linkage disequilibrium that exists between multiple genes in this chromosomal region.[16]

The DLG5 Gene

Two haplotypes of DLG5, which encodes a scaffolding protein that helps to maintain epithelial integrity, have been associated with Crohn's disease and combined ulcerative colitis and Crohn's disease populations.[17] Like the OCTN1 and OCTN2 variants, the 113G>A substitution in DLG5 is associated with CARD15 mutations in patients with Crohn's disease. The association of the 113A DLG5 allele with Crohn's disease has been confirmed.

The MDR1 gene

The multidrug resistance gene MDR1 encodes P-glycoprotein 170, a transporter that governs efflux of drugs and possibly xenobiotic compounds from cells. P-glycoprotein 170 might also function as a 'flippase' that moves amphipathic substrates from the inner to the outer leaflet of the cell membrane. MDR1 variants have been associated with ulcerative colitis[18] and Crohn's disease.[19]MDR1 is of particular interest, because it has been associated with treatment-refractory IBD,[20] and because mice in which Mdr1 has been deleted develop colitis.[21] Bone-marrow-transplantation studies have implicated epithelial and/or mesenchymal cells in the pathogenesis of colitis in Mdr1-deficient mice.

The PPARG Gene

PPARG (peroxisome proliferative-activated receptor γ) variants have been linked with susceptibility in the SAMP1/YitFc mouse model of spontaneous chronic ileitis, and rare PPARG polymorphisms were found to be associated with human Crohn's disease.[22] PPARγ is a nuclear receptor that inhibits NFκB activity: its expression is decreased in patients with active ulcerative colitis[23] and its expression is upregulated by 5-aminosalicylic acid.[24] In addition to a potential role in protecting against intestinal inflammation, treatment with the PPARγ ligand rosiglitazone was effective in an open-label trial involving ulcerative colitis patients[25] as well as in mouse experimental colitis.[26]

Summary

To date, four genes have been associated with Crohn's disease and one with ulcerative colitis; these data have been replicated. Strong associations with other chromosomal regions and genes (e.g. NFκB1, TLR5) have yet to be replicated, but such associations make it highly likely that many additional genes will be implicated in the pathogenesis of IBD, while others will be associated with extraintestinal disease (e.g. HLA-B27 and HLA-DR0103 human leukocyte antigen haplotypes, etc.) and with responses to pharmacologic treatment (i.e. pharmacogenomics). The genes associated with the pathogenesis of IBD regulate innate immune responses, mucosal barrier function and bacterial killing.

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