PGN derived from the walls of commensal bacteria is sensed by TLR2 on the surface of dendritic cells in the intestinal lamina propria (left inset). This leads to TLR2 ligation and the downstream activation of NF-κB, the key transcription factor necessary for the differentiation of cells producing IFN-γ and IL-17, the proinflammatory cytokines responsible for Crohn disease. PGN, however, is also broken down in endosomes and is thus a source of MDP, a substance that is sensed by and activates NOD2. Such activation initiates a mechanism of inhibition of PGN-mediated NF-κB activation and thus causes downmodulation of TLR-induced cytokine production. In patients with Crohn disease bearing NOD2 mutations (right inset), the NOD2 modulation is impaired, and hence the innate immune “thermostat” of the intestine is set at a higher level of proinflammatory cytokine production. This, together with a tendency of T cells to react to mucosal antigens, leads to inflammation and disease. An additional factor relates to the function of α-defensins, antibacterial peptides produced by Paneth cells at the base of crypts in the terminal ileum (middle inset). Crohn disease patients with impaired NOD2 function manifest reduced α-defensin production in part because NOD2 in Paneth cells is an inducer of α-defensin production. Thus, it is possible that impaired NOD2 function also leads to increased bacterial density in the crypts of the terminal ileum and thus greater stimulation of a mucosal immune system already set at a higher level of function.