Today, it is known that Nod2 expresses a protein that recognizes a building block of bacterial cell walls, called muramyl dipeptide (MDP), effectively making it a bacterial sensor. Nod2 is expressed primarily by bone-marrow-derived macrophages. In addition, the protein NOD2 appears to play a role in the activation of NF-B, a major regulator of the production of pro-inflammatory cytoines such as tumour necrosis factor- (TNF) and interleukin IL-1ß. The relation is relevant because patients with Crohn's disease overproduce NF-B and cytokines, and anti-inflammatory drugs represent the mainstays of treatment. Nevertheless, how Nod2contributes to the pathology of Crohn's disease has been an open question — one that the modelling of the disease in mice is beginning to answer.
The results of these studies help to explain the association between Nod2 mutations and Crohn's disease. In finding Nod2 to be an important immune mediator in the intestine, the studies also fuel the notion that bacterial infection is an important pathogenetic factor. Indeed, as Kobayashi and colleagues suggest, Nod2 mutations may not play a directly causative role but, rather, may create an environment in the gut that renders it susceptible to Crohn's disease. Further research is required to confirm this and to elucidate the link between Nod2 mutations and -defensin, one that has already been established in humans.6 It is hoped that the results of this research will open future therapeutic avenues.