Growing evidence suggests that inflammatory bowel disease is the result of a dysregulated immune response to common luminal flora. The intestinal inflammation of IBD may be viewed as an exaggeration of the 'physiological' inflammatory response always present in the normal lamina propria of the intestine and colon.103 An intact mucosal barrier and regulatory mechanisms normally prevent the immune and inflammatory responses from causing tissue injury.103 A defect in either mucosal barrier function, antigen processing or immunoregulation could result in a chronic inflammation, lymphocyte proliferation, cytokine release, neutrophil recruitment and tissue damage.103 The factors that trigger activation of the immune system are unclear, but could be related to an intrinsic defect (either constitutive activation or the failure of down-regulatory mechanisms) or ongoing stimulation resulting from a change in the epithelial mucosal barrier.2
Data from studies on tissue samples from patients with IBD and experimental animal models of colitis have demonstrated unbalanced Th1 vs. Th2 responses in the intestinal mucosa.84,104,105 The mucosa of patients with established Crohn's disease is dominated by CD4+ lymphocytes with a Th1 phenotype, characterized by the production of interferon-y and interleukin (IL)-2;2 whereas the mucosa in patients with ulcerative colitis may be dominated by CD4+ lymphocytes with an atypical Th2 phenotype, characterized by the production of transforming growth factor (TGF)-P and IL-5, but not IL-4.2 CD4+ lymphocytes clearly play an important role in the pathogenesis of tissue damage in inflammatory bowel disease, particularly in Crohn's disease.84,106 Patients with disorders such as glycogen storage disease 1b, which are associated with abnormalities in neutrophil function may exhibit clinical manifestations of IBD. These observations suggest that the mechanisms leading to mucosal injury are not always lymphocyte dependent.
Loss of tolerance towards the luminal commensal bacterial flora appears to be an important factor in the pathophysiology of IBD. Concomitant decrease of production of TGF-P and IL-10 by regulatory T lymphocytes may be partially responsible for the loss of tolerance to luminal flora and activation of
Th1 cells.107-109 Results from murine studies have shown that Th1 cytokines activate macrophages, which in turn, produce IL-12, IL-18 and macrophage migration inhibitor factor, thereby stimulating a Th1 response in a self-sustaining cycle.110,111 Activated macrophages produce a variety of potent proinflammatory cytokines including tumor necrosis factor (TNF)-a, IL-1 and IL-6. TNF-a has a variety of biological effects, including: macrophage activation and induction of protease, both of which can play a role in tissue destruc-tion;112 up-regulation of adhesion molecule expression, facilitating recruitment of monocytes, lymphocytes and granulocytes;113 enhancement of chloride secretion from intestinal epithelial cells;114 increase of epithelial cell permeability;115 and enhancement of production of acute-phase reactants.112 The inflammatory process and tissue destruction of the intestine are further promoted by generation of various proinflammatory mediators including other cytokines, chemokines, growth factors, arachidonic acid metabolites (prostaglandins and leukotrienes) and reactive oxygen metabolites such as nitric oxide.2 Activation of this destructive process results in the mucosal injury and clinical manifestations of IBD.
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Everyone has an upset stomach from time to time. You probably know the sort of thing I mean – sometimes you’ve got gas and at other times you feel queasy or nauseous. There may be times<br />when you can’t seem to go to the toilet for days, constipated as can be, but there are other days when diarrhea strikes and you can’t stop going!