One of these, the L1007insC frameshift mutation (31% prevalence), results in a truncated NOD2 protein lacking part of the last LRR. Homozygous carriers of this mutation exhibit a much more severe disease phenotype and have a higher Selleckchem Afatinib risk for ileal stenosis and surgical intervention

42. A different subset of CARD15 mutations cause a distinct and highly penetrant autosomal dominant systemic disorder called Blau syndrome (BS) 43. BS mutations almost exclusively target the NBD of the protein and produce a broader distribution of affected tissues than CD. Three-dimensional structure analysis predicted that the NLRP3 R260W mutation and the BS-associated R334W mutation of NOD2 encode a substitution at a homologous, structurally conserved amino acid residue 44. Therefore, as is the case for NLRP3 in CAPS, NBD mutations in BS may produce a protein that is constitutively active, a hypothesis Autophagy activator supported by the finding that R334W NOD2 leads to increased basal NF-κB activation 45. As LRRs are implicated in sensing microbial components, CD-associated mutations in NOD2 may alter the threshold of mycobacterial N-glycolyl muramyl dipeptide recognition and its downstream signalling rather than lead to a constitutively active form as in BS. However, the consensus mechanism by which mutations in NOD2 predispose

to CD remains controversial. Indeed, Segal and colleagues have reported that CD patients, irrespective of their genotype, share a dampened inflammatory phenotype in response to injury or bacterial challenge 46. Enhanced lysosomal degradation

was proposed to be at the basis of the cytokine secretion defect in CD. This raises the question of whether CD is a systemic immune deficiency disease with manifestations in the intestinal tract due to the uniquely high bacterial content of this organ. Only recently did a study reveal the surprising discovery that, unlike its WT counterpart, L1007insC mutant NOD2 actively suppresses the constitutive transcription of human IL-10 Cyclooxygenase (COX) in a peptidoglycan- and NF-κB-independent manner by inhibiting the activity of hnRNP-A1 in monocytes 47. This phenomenon was not found with the mouse orthologues and cautions on the necessity of human functional immunological studies. In this context, it is not surprising that enhanced IL-10 production, which can occur after treatment with certain probiotic bacteria, helps to calm inflammation in CD 48. Such data suggest a complex interaction between NOD2 and a number of other loci controlling innate and adaptive immune function (e.g. IL-23R 49) to confer susceptibility to CD. Nonetheless, these studies provide initial evidence in support of a long-held theory that conjectures that NOD2 normally functions as an innate signal that tolerizes the host’s adaptive immune system to the commensal intestinal flora. Although there are limitations inherent to GWAS design (e.g.