PATHOGENESIS AND IMMUNE-MECHANISMS OF CHRONIC INFLAMMATORY BOWEL DISEASES

The inflammatory bowel diseases (IBDs) are characterized by intestinal inflammation of unknown etiology. Two distinct disorders, Crohn's dis ease and ulcerative colitis, have been identified. Three theories of I BD etiology are currently under consideration: 1) reaction to a persis tent intestinal infection, 2) existence of a defective mucosal barrier to luminal antigens, and 3) a dysregulated host immune response to ub iquitous antigens. In each of these theories, either pathogenic or res ident luminal bacteria constantly stimulate the mucosal and systemic i mmune systems to perpetuate the inflammatory cascade. Chronicity of in flammation results from an interaction of the persistent stimulus of m icrobial antigens with genetically determined host susceptibility fact ors that determine the individual's immune response or mucosal barrier function. The pathogenesis of IBD involves a series of steps, beginni ng with the breach of the intestinal mucosal barrier by infectious age nts or toxins. The defective barrier exposes lamina propria immune cel ls to the continual presence of resident luminal bacteria, bacterial p roducts, or dietary antigens, which perpetuates the inflammatory casca de. Many immunoregulatory abnormalities are noted in IBD, including th e ratio of proinflammatory to immunosuppressive cytokines, selective a ctivation of T-H lymphocyte subsets, and abnormalities in epithelial a ntigen presentation. When activated during the initial inflammatory pr ocess, macrophages and T lymphocytes secrete a host of cytokines, whic h recruit other inflammatory cell types, thereby continuing the proces s. Tissue injury is the net result of the soluble products of the acti vated inflammatory cells. Knowledge of the pathogenesis in IBD suggest s that the ultimate goals of therapy should be to block the proinflamm atory mediators toward the proximal, rather than the distal, end of th e cascade, to decrease the constant antigenic drive of luminal bacteri a, and to correct the dysregulated immune response.