Crohn's disease - role of CARD15/NOD2?
Crohn's disease (CD) is a chronic inflammatory disease of the intestines. CD primarily causes ulcerations in the small and large intestines, but can affect the digestive system anywhere between the mouth and the anus (for a possible pathogenic role of cytokines, click here).
CD is a polygenic disorder, i.e. several genes are associated with the disease. One of these, the CARD15/NOD2 gene on chromosome 16, seems of special importance. Mutations in CARD15 is the cause of Blau's syndrome, a systemic granulomatous inflammatory disease of dominant inheritance. However, mutations in the same gene has recently been shown to increase the risk of developing CD. However, the mutational sites in CARD15 are different in patients with CD and Blau's syndrome, the former usually being located in the leucine-rich repeat (LRR) domain or in its immediate vicinity (see figure). Interestingly, the LRR domain of the intracellular CARD15 protein senses a muramyl dipeptide (MDP) motif on a fragment of peptidoglycan (PG), which is a major component of the cell wall of gram-positive bacteria (it is also found in the periplasmic space in gram-negative bacteria). CARD15 is under regulation by inflammatory cytokines, such as TNFalpha and IFN-gamma.