Update on the pathophysiology of inflammatory bowel disease

Abstract

Crohn's disease (CD) and Ulcerative colitis (UC) comprise a series of inflammatory bowel disease (IBD) resulting from chronic up-regulation of the mucosal immune system. Although the pathogenesis of IBD remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals, which are directed by genetic factors, immunological factors, and environmental factors such as foods and enteric microbes. Regarding genetic factors, important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for CD. New data on CARD15/NOD2 function and nuclear factor-κB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional “innate” pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The “germ concept” and the “genetic concept” of IBD pathophysiology are converging. The evidence continues to accumulate that CD is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarization. T-cell resistance to apoptosis occurs in CD, and human and mouse studies indicate that the signaling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Progress in understanding the pathophysiology of UC remains slow, but IL-13 produced by natural killer T cells may be involved. There is a possibility that UC might be a sort of syndrome such as viral/bacterial infectious diseases and autoimmune disorders. Despite the evidence of a role for Th1 in CD, support for a Th2 pathogenesis in ulcerative colitis is much weaker. The presence of autoantibodies, such as anticolon antibody, antimucin antibody, or antitropomyosin antibody, is suggestive of a Th2 pathogenesis. There are several conflicting immunological findings, but some immunological abnormalities may induce colonic inflammation.