Advances and Perspectives in the Genetics of Inflammatory Bowel Diseases  Mathias Chamaillard, Razvan Iacob, Pierre Desreumaux, Jean–Frederic Colombel  Clinical Gastroenterology and Hepatology  Volume 4, Issue 2, Pages 143-151 (February 2006) DOI: 10.1016/j.cgh.2005.11.008 Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 1 Overview of the IBD-susceptibility and IBD-modifying genes in human beings. The confirmed and suggested IBD-susceptibility loci are indicated by black and grey rectangles, respectively. The confirmed and suggested IBD-susceptibility genes are indicated by black and grey letters, respectively. Clinical Gastroenterology and Hepatology 2006 4, 143-151DOI: (10.1016/j.cgh.2005.11.008) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 2 Host-dependent and environmental-dependent steps from bacterial exposure toward clinical expression of IBD. Gene-gene and gene-environment interactions may affect multiple clinical (ie, disease onset, location of the initial lesions, and severity) and biological (ie, serology to microbial antigen) aspects of the disease. Clinical Gastroenterology and Hepatology 2006 4, 143-151DOI: (10.1016/j.cgh.2005.11.008) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 3 Gain- or loss-of-CARD15/NOD2 function in CD. (A) Muramyl dipeptide–induced NF-κB activation in myeloid and Paneth cells is dependent on CARD15/NOD2. (B) The loss-of-function hypothesis is suggested by human and mice data using peripheral blood monocytes from mutated patients and knock-out mice. Such scenarios might be complemented by activating downstream molecules of CARD15/NOD2 (ie, specific RIP-like interacting CLARP kinase agonist) and/or by stimulating impaired gene expression by the CARD15/NOD2-independent signaling pathway (stimulated by probiotics and/or vaccine adjuvants). (C) CARD15/NOD22939iC/2939iC bone-marrow–derived macrophages showed a hypersensitivity to the CARD15/NOD2 agonist, suggesting the gain-of-function hypothesis. If this situation is confirmed, anti-inflammatory molecules could be proposed. Clinical Gastroenterology and Hepatology 2006 4, 143-151DOI: (10.1016/j.cgh.2005.11.008) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 4 Implications of decreased TLR and NOD-LRR signaling for future therapies. Specific molecules acting on redundant signaling pathways (probiotics and PRM agonists are shown as (1) and (2), respectively) or downstream of the functional defect (PRM kinase agonist, IkappaB kinase agonist, and nuclear receptor agonists are shown (3), (4), and (5), respectively) could complement TLR and/or NOD-LRR deficiencies (noted in gray), as shown by decreased gene expression. Several therapeutic molecules and their proposed targets of action are indicated. (A) Normal innate immune signaling; (B) decreased innate immune signaling. Clinical Gastroenterology and Hepatology 2006 4, 143-151DOI: (10.1016/j.cgh.2005.11.008) Copyright © 2006 American Gastroenterological Association Terms and Conditions