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  • Gut-associated lymphoid tissues (GALT) are characterized by a unique structure, physiologic inflammation, a tendency to suppress immune responses (oral tolerance), and production of secretory immunoglobulins.

  • The immune response has two major arms: innate (rapid, hard-wired) and adaptive (delayed in onset with memory).

  • Inflammatory bowel disease (IBD) offers a paradigm for understanding and treating intestinal inflammatory diseases.

  • IBD is a dysregulated immune response of GALT to normal commensal microbes within the intestine; risk of IBD is altered by genetic susceptibility and by specific environmental factors (eg, tobacco).

  • Numerous genetic loci and environmental elements defined as risk factors for IBD regulate innate and adaptive immunity, the epithelial barrier, and the relationships of each of these with normal commensal microbiota (bacterial and nonbacterial).

  • IBD is ultimately caused by overproduction of proinflammatory mediators relative to anti-inflammatory mediators, both of which are derived from cells associated with adaptive immunity (T helper [Th] cells) and innate immunity (macrophages and dendritic cells) that excessively infiltrate the intestinal tissues.

  • Although Crohns disease (CD) may preferentially exhibit overactivity of Th1 and Th17 cells, and ulcerative colitis (UC) may exhibit overactivity of Th2 cells, there is significant overlap in the immunopathogenesis of these disorders.

  • Excess production of cytokines derived from innate immune pathways (tumor necrosis factor [TNF] and interleukin-6 [IL-6]) occurs in both CD and UC.

  • T regulatory cells secrete anti-inflammatory cytokines (eg, IL-10, transforming growth factor-β [TGFβ], and IL-35) that inhibit proinflammatory cytokine responses from innate and adaptive immune cells.

  • Increased understanding of IBD immunopathogenesis has led to development of therapeutic agents that are increasingly being administered in a logical, mechanism-based manner.


General Considerations


Clinically, IBD is a chronic inflammatory condition of the intestines that is marked by remission and relapses and distills clinically into one of two major subtypes of disease: UC and CD. Both diseases have a general commonality in their pathogenesis and are derived from a dysregulated mucosal immune response to antigenic components of the normal commensal microbiota that reside within the intestine (Figure 2–1).

Figure 2–1.

Pathophysiologic mechanisms of inflammatory bowel disease (IBD). IBD represents the dysregulated mucosal immune response to commensal microbial antigens that is modified by genetic and environmental risk factors. At its core, IBD derives from dysfunctional bidirectional interactions between the commensal microbiota, the intestinal epithelial cells, and the immune system components within the epithelium and lamina propria. Numerous genetic and environmental factors have been identified that modify the risk for IBD development by specifically affecting the composition and function of the aforementioned critical core elements of disease pathogenesis (commensal microbiota, intestinal epithelium, or immune system). Examples of factors that are involved in these pathways are shown. HSP, heat shock proteins; NSAID, nonsteroidal anti-inflammatory drugs; PRR, pattern recognition receptors; RA, retinoic acid; ROS, reactive oxygen species; TSLP, thymic stromal lymphopoietin; Genes’ names in red are Crohn disease specific, blue are ulcerative colitis specific, and black are those that affect both ...

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