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Figure 9.25 SNP markers show association with IL23Rat 1p31. Data for SNPs from combined case-control cohorts were analysed by Duerr and colleagues. Negative log10 associated P values are shown together with a pairwise r2 plot for individuals of European geographic ancestry from the CEU HapMap panel, demonstrating discrete haplotypic blocks with no association in the block spanning neighbouring gene IL12RB2. Adapted from Duerr et al. (2006), reprinted with permission from AAAS. Gene plots with genomic location adapted from screenshot of UCSC Genome Browser (Kent et al. 2002) (http://genome.ucsc.edu/) (Human May 2004 Assembly).

Figure 9.25 SNP markers show association with IL23Rat 1p31. Data for SNPs from combined case-control cohorts were analysed by Duerr and colleagues. Negative log10 associated P values are shown together with a pairwise r2 plot for individuals of European geographic ancestry from the CEU HapMap panel, demonstrating discrete haplotypic blocks with no association in the block spanning neighbouring gene IL12RB2. Adapted from Duerr et al. (2006), reprinted with permission from AAAS. Gene plots with genomic location adapted from screenshot of UCSC Genome Browser (Kent et al. 2002) (http://genome.ucsc.edu/) (Human May 2004 Assembly).

These genetic studies, added to a range of other data from animal models and studies of affected patients, suggest IL23 may play a critical role in the pathogenesis of inflammatory bowel disease (Neurath 2007). IL23 is an important proinflammatory cytokine made up of two subunits, p19 (encoded by IL23A) and p40 (encoded by IL12B) (Fig. 9.26). Antibodies to p40 block both IL12 and IL23 signalling, and were shown to suppress inflammation in an animal model of Crohn's disease (Neurath et al. 1995) and to significantly improve clinical response and remission in active human disease (Mannon et al. 2004). Antibodies to p19 or a knock-out also suppress intestinal inflammation in mouse models and it is thought that IL23 plays an important role in both innate and

T cell mediated inflammation occurring in the intestine, central to inflammatory bowel disease pathogenesis (Neurath 2007). Fundamental to this may be the role of IL23 in activating T helper 17 lymphocytes producing interleukin-17, a key mediator of chronic inflammation found at high levels in the intestinal mucosa of patients with Crohn's disease (Fujino et al. 2003); pathogenesis may also involve effects of IL23 on mucosal barrier function (Cho 2008).

Interest in the role of the IL23R pathway in disease pathogenesis is further highlighted by the finding that SNPs in IL12B at chromosome 5q33 (encoding the p40 subunit shared by IL23 and IL12), STAT3 at chromosome 17q21 (encoding signal transducer and activator of

IL-23 p40* p19

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