Genetic contribution of TLR signaling in the pathogenesis of IBD

IBD is thought to result in the genetically-susceptible host following a triggering event. Genetic factors play a more dominant role in Crohn's disease than ulcerative colitis based on accumulated data from identical twin studies and familial clustering [58]. Polymorphisms in the NOD2/CARD15 gene (R702W, G908R and 1007fs) have been identified in patients with Crohn's disease [59, 60]. Nucleotide oligomer-ization domain (Nod) proteins are PRRs with homology to plant disease resistance proteins [61, 62], which confer responsiveness to peptidoglycan through Rip2/RICK kinase, a mediator of NF-kB activation [63-65]. Approximately a third of patients with Crohn's disease carry one of three allelic variants of NOD2/CARD15 compared with 10-15% of the normal population or ulcerative colitis patients [66-69]. Homozygosity increases the relative risk of developing Crohn's disease by as much as 40-fold as compared to simple heterozygosity [59, 70, 71]. Clinical phenotypic associations with NOD2/CARD15 mutations include a slightly younger age of onset, ileal involvement, and fibrostenotic disease [72-75]. Children with mutations in NOD2/CARD15 have an accelerated course towards their first surgery [76]. Nod2 protein is highly expressed by monocytes and Paneth cells [77] and is also seen in the inflamed colon in Crohn's disease [78]. Polymorphisms in this gene result in a decreased ability to bind to the bacterial ligand, muramyl dipeptide (MDP), and altered activation of the NF-kB system leading to a reduced capacity to activate proinflammatory signals in the presence of intracellular bacteria [63, 79].

Initially it was difficult to reconcile why those mutations would increase susceptibility to a disease characterized by exuberant inflammation in response to commensal bacteria. Cytokine production in response to MDP is abolished in Nod2 knockout (Nod2-/-) mice and they do not develop any intestinal pathological changes spontaneously [80, 81]. More recently, Nod2 appears to play an important role in innate immunity against pathogens. Nod2-/- mice have low levels of crypt-din expression by Paneth cells [39]. When these mice are orally infected with Listeria monocytogenes, there is dissemination of the Listeria that is not seen with wildtype mice. More germane to the issue of IBD, mice carrying a mutation that is analogous to the Crohn's disease susceptibility allele, 3020insC, exhibit elevated NF-kB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1p [51]. In addition, mice carrying the Crohn's disease-associ ated Nod2 mutation are more susceptible to DSS-induced colitis with greater expression of proinflammatory cytokines [51]. Although these findings in the animal model are interesting, the induction of acute inflammation with DSS is quite dissimilar to the ileal inflammation seen in patients with Crohn's disease. On the other hand, patients homozygous for the 3020insC frameshift-mutation in the Nod2 gene demonstrate defective release of IL-10 from peripheral blood mononu-clear cells after stimulation with TLR2 ligands [82]. Thus, in the setting of Crohn's disease-associated mutations of Nod2, TLR2 signaling is associated with diminished secretion of anti-inflammatory cytokines. Another model for why mutations in Nod2 may predispose to Crohn's disease is through aberrant clearance of intracel-lular pathogens, since overexpression of Nod2 in intestinal epithelial cells protects against Salmonella typhimurium in vitro [83]. Studies examining NOD2 mutations in Japanese, Korean and African-American individuals with Crohn's disease have not shown an association [84-86]. Therefore other genes await identification as IBD-susceptibility genes.

TLR genes may be candidate genes for IBD, while recent studies have demonstrated mixed results with respect to the association between the TLR4 polymorphisms and IBD. Two common co-segregating missense mutations in the extracellular domain of TLR4, Asp299Gly and Thr399lle, have been found to result in diminished response to inhaled LPS and protection against atherosclerosis [87-89]. The allele and carrier frequencies for the Thr399Ile mutation in the TLR4 gene were positively associated with ulcerative colitis in a German population [90]. In addition, association of the TLR4 Asp299Gly polymorphism was found in both Crohn's disease and ulcerative colitis in a Belgian population [91]. However, TLR4 (A299G) and CD14 (T-159C) variants did not differ between Crohn's disease and controls in Scottish and Irish patients [92]. A recent study in Japanese patients with ulcerative colitis yet again failed to detect any increase in TLR4 polymorphisms in IBD patients [93].

Additional genetic evidence points to the recognition of PAMPs in the pathogenesis of IBD. Polymorphisms in the IL-1 receptor antagonist gene may affect severity and extent of disease in ulcerative colitis patients, particularly in patients positive for perinuclear antineutrophil cytoplasmic antibody (pANCA) [94]. In addition, a common functional promoter region polymorphism (T-159C) of the CD14 gene has been identified and has a weak association with both Crohn's disease and ulcerative colitis in German and Japanese patients [95, 96]. These studies imply a role of innate immune response genes in the pathogenesis of IBD.

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