Abstract
BACKGROUND: Crohn's disease and ulcerative colitis are chronic inflammatory disorders associated with a dysregulated adaptive and innate immune response to gut commensals in genetically susceptible individuals. The pathogenesis of inflammatory bowel disease is complex, and the disease is characterized by significant phenotypic and genotypic heterogeneity. SUMMARY: The introduction of anti-TNF biologics has resulted in improved clinical outcomes in patients with severe and moderately severe disease, but the current treatment paradigm continues to depend on systemic immunosuppression (steroids and immunomodulators) and surgical intervention in a significant number of patients, underscoring a significant unmet need. More recently, a number of genetic and immunologic abnormalities have been unraveled including aberrant intestinal mucosal defense function, abnormal intestinal permeability, dysregulated bacterial antigen processing by macrophages and presentation to T cells, cellular immune regulation and signaling, cytokine production, and leukocyte trafficking. KEY MESSAGES: Understanding these molecular mechanisms and effector pathways presents an opportunity for the development of new and improved targeted therapies.