Pathogenesis of Inflammatory Bowel Diseases

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively called inflammatory bowel disease (IBD), are idiopathic, chronic, and relapsing intestinal inflammatory disorder, characterized by abdominal pain and diarrhea. UC differs dramatically from CD with the respects of disease distribution, morphology, and histopathology; for example, CD can affect any part of the gastrointestinal (GI) tract, usually discontinuously. UC is confined to the colon, it is characterized by continuous inflammation, invariably involving the rectum, and is classified according to its proximal limit (proctitis, distal, or extensive colitis). Further, unlike CD, inflammation in UC is restricted to the mucosal surface, perhaps giving weight to the emerging concept of a defective mucosal barrier in disease pathogenesis. Histologically active UC typically consists of a neutrophilic mucosal infiltrate, goblet cell depletion, ‘‘cryptitis,’’ and prominent crypt abscesses. Acute inflammatory process in UC is associated with mucosal (particularly epithelial) cell destruction. Meantime, UC and CD share a lot of inflammatory similarities, such as epithelial barrier dysfunction, genetic susceptibility etc. IBD may result in significant morbidity and mortality, with compromised quality of life and life expectancy. While there is no cure for IBD, the last two decades have seen tremendous advances in our understanding of the pathophysiology of this intestinal inflammation. Even though the precise etiology of IBD remains elusive, it is accepted (Figure 1) that IBD arises from abnormal host–microbe interactions, including qualitative and quantitative changes in the composition of the microbiota, host genetic susceptibility, barrier function, as well as innate and adaptive immunity. In more detail, some defects occur in luminal bacterial antigen sampling by the epithelium, possibly mediated by toll-like receptors (TLRs) or nucleotide binding oligomerisation domain family (NODs), controlled by genetic factors (including NOD2 for CD etc). An over-response to the antigens then stimulates activated dendritic cells to generate Th1-type /Th17 T cells or Th2-type /NK T cells, which then generate cytokines, initiating a cascade of immunologic events resulting in tissue damage. Thus, the factors participating in what manifests as inflammation in UC and CD are part of a dynamic process in which autoantibodies are generated against mucosal antigens in a susceptible host. The autoantibodies are not primarily responsible for disease pathogenesis; rather, they mark for disease-related autoantigens, which likely cross react with bacterial antigens from the normal intestinal flora. In a genetically susceptible host, the interaction results in an exaggerated inflammatory response in which either a lack of regulatory cells or enhanced numbers of effector cells initiates disease. With time, antigenic spreading to host antigens (the autoantigens) occurs; therefore, removal of these bacteria would no longer affect disease activity (Vanderlugt et al., 1996).