As noted earlier in this chapter, Crohn’s disease (CD) is one of the two major types of inflammatory bowel disease. CD is thought to result from abnormal hyperresponsiveness of CD4 T cells to antigens of the commensal gut microbiota, rather than to true self antigens. Dysregulation of TH17 and TH1 cells is thought to be pathogenic. Disease can result from a failure of mucosal innate immune mechanisms to sequester luminal bacteria from the adaptive immune system, from T-cell-intrinsic defects that cause heightened effector responses, or from failure of Treg cells to suppress microbiota-reactive TH17 and TH1 cells (Fig. 15.41). Patients with CD have episodes of severe inflammation that commonly affect the terminal ileum, with or without involvement of the colon—hence the alternative name ‘regional ileitis’ for this disease—but any part of the gastrointestinal tract can be involved. The disease is characterized by chronic inflammation and granulomatous lesions in the mucosa and sub-mucosa of the intestine. Genetic analysis of patients with CD and their families has identified a growing list of disease-susceptibility genes (see Fig. 15.34). One of the earliest to be identified was NOD2 (also known as CARD15), which is expressed predominantly in monocytes, dendritic cells, and the Paneth cells of the small intestine, and is involved in recognition of microbial antigens as part of the innate immune response (see Section 3-8). Mutations and rare polymorphic variants in NOD2 are strongly associated with CD. Mutations in the same gene are also the cause of a dominantly inherited granulomatous disease named Blau syndrome, in which granulomas typically develop in the skin, eyes, and joints. Whereas CD results from a loss of function of NOD2, it is thought that Blau syndrome results from a gain of function.
goblet cell intestinal epithelial cells homeostatic dendritic cell TregTH17TH1 anti-infammatory activated phagocytic cell macrophage auto-phagosome (ATG16L1 IRGM) Paneth cell antimicrobial peptides NOD2 bacteriaintestinal lumen mucus layer intestinal lamina propria pro-infammatory IL-6, TGF-˜IL-1˜, IL-23 TGF-˜RAIL-12
NOD2 is an intracellular receptor for the muramyl dipeptide derived from bacterial peptidoglycan, and its stimulation activates the transcription factor NFκB and the expression of genes encoding pro-inflammatory cytokines and chemokines (see Section 3-8 and Fig. 12.15). In Paneth cells—specialized intestinal epithelial cells in the base of the small intestinal crypts—activation of NOD2 stimulates the release of granules containing antimicrobial peptides that help sequester commensal bacteria to the intestinal lumen, away from the adaptive immune system. Mutant forms of NOD2 that have lost this function limit this innate antibacterial response, thereby predisposing the individual to heightened effector CD4 T-cell responses to the commensal microbiota and consequent chronic intestinal inflammation (see Section 12-22).