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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 intestines of a genetically susceptible host; this response is modified by specific environmental factors (eg, tobacco).
  • Numerous genetic loci defined as risk factors for IBD regulate innate immunity, 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).
  • Crohn disease (CD) preferentially exhibits overactivity of Th1 and Th17 cells, and ulcerative colitis (UC) may exhibit overactivity of Th2 cells.
  • 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 anti-inflammatory therapeutic agents that are increasingly being administered in a logical, mechanism-based manner.

Clinically, inflammatory bowel disease (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: ulcerative colitis (UC) and Crohn disease (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 in a genetically susceptible host (Figure 2–1).

Figure 2–1.

Pathophysiologic mechanism of inflammatory bowel disease (IBD). IBD represents the dysregulated mucosal immune response to commensal microbial antigens in a genetically susceptible host that is modified by environmental factors. An exaggerated T-cell response of polarized T cells that secrete T helper (Th) 1, 2, or 17 cytokines causes tissue injury and clinical symptoms. An inadequate T regulatory cell response is likely to be a significant contributor to IBD pathogenesis. OCPs, oral contraceptive pills.

This tripartite interaction between the genetic composition of the host, the mucosal immune response (including that associated with the epithelial barrier), and its relationship to the commensal microbiota is likely further modified by specific environmental factors that affect the lifetime risk of developing this disorder. Although the influence of specific gene variations, as endogenous risk factors that clearly define susceptibility to this disease, is well accepted, only a limited number of environmental factors have clearly been proven to either modify these diseases ...

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