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Activation

Figure 1 Possible activating events In IBD. Bacterial cell wall products, infectious agents and/or toxins can be transported across M cells or presented by class II antigens on epithelial cells to prime and activate macrophages. After antigen presentation, the primed and activated macrophages synthesize and secrete a variety of molecules including proinflammatory cytokines, such as IL-1, IL-6 and TNFa. The proinflammatory cytokines in turn activate a number of cell-mediated events and processes, including activating CD4' T helper cells in the intestine. In IBD, macrophages and lymphocytes are in a highly activated and upregulated state with the resultant secretion of proinflammatory and immunoregulatory molecules. (Adapted with permission from Reinecker H-C, Schreiber S. Stenson WF and MacDermott RP (1994) The role of the mucosal immune system in ulcerative colitis and Crohn's disease. In: Ogra PL, Mestecky J, Lamm ME, Strober W, McGhee JR and Bienenstock J (eds) Handbook of Mucosal Immunology p440. London: Academic Press.)

patients. Crohn's disease peripheral blood mononuclear cells have an enhanced capacity to secrete soluble IL-2 receptor, both spontaneously and after stimulation with phytohemagglutinin (PHA) in vitro. The increased capacity of mononuclear cells isolated from intestinal lamina propria to release soluble 1L-2 receptor is not specific to 1BD because similar findings have been observed in colonic diverticulitis. Nevertheless, increased serum levels of soluble IL-2 receptor in Crohn's disease patients correlate with intestinal inflammatory activity, and the receptor is detected in the portal venous system from inflamed intestine of Crohn's disease patients. These studies, therefore, demonstrate that activated lymphocytes in IBD may be a central feature of the immunological changes that result in inflammation (Figure 2). Measurement of such activation molecules provides a useful marker to correlate the level of tissue inflammation with ongoing disease activity.

Intestinal lymphocytes

Immunohistological studies of the inflammatory cells in IBD mucosa have yielded conflicting results regarding intestinal lymphocyte activation in

Crohn's disease and ulcerative colitis. A number of workers have demonstrated the increased expression of lymphocyte activation antigens, such as 4F2, transferrin receptor, IL-2 receptor, and HLA-DR in Crohn's disease and ulcerative colitis, whereas other groups have failed to do so. Studies by James and colleagues found that IL-2 mRNA levels were elevated in the mucosa of patients with Crohn's disease but not ulcerative colitis. In contrast, Allison and colleagues demonstrated the appearance of the CD7 activation marker but no increase in IL-2 receptor expression. Studies examining flow cytometric analysis of isolated colonic lamina propria mononuclear cells revealed increased expression of activation markers, including IL-2 receptor, transferrin receptor, and the 4F2 antigen on intestinal B and T cells as well as CD4" and CD8+ T lymphocyte subpopula-tions in both active ulcerative colitis and Crohn's disease. These studies provide evidence that activation of B and T cell lymphocyte populations occur in the intestine as well as in the peripheral blood of patients with IBD.

Figure 2 Cell-mediated immunity in IBD. After luminal bacterial cell wall products lead to macrophage activation, specific antigen presentation occurs, resulting in the activation and expansion of CD4+ T helper lymphocytes. The activation of T helper cells leads to enhanced B cell proliferation and maturation, resulting in increased numbers of IgG-producing plasma cells. Resultant secretion of soluble IL-2 receptor by activated mucosal lymphocytes involved in the inflammatory process leads to increased levels of circulating soluble IL-2 receptor, which can be found to correlate with disease activity. In the normal intestine, the predominant immunoglobulin isotype secreted by B cells is IgA, which protects against pathogens by antigen exclusion. IgA overall increase in IgG-secreting lamina propria B cells has been demonstrated. In marked contrast to IgA, IgG is capable of fixing complement, arming NK cells and activating phagocytes. The increase in IgG subclasses is composed primarily of lgG1 and lgG3 in ulcerative colitis, whereas in Crohn's disease the increase is predominantly in lgG1 and lgG2. (Adapted with permission from Screiber S, Raedler A, Stenson WF and MacDermott RP (1992) The role of the mucosal immune system in inflammatory bowel disease. In: MacDermott RP and Elson CO (eds) Gastroenterology Clinics of North America, 21: 453. Philadelphia: WB Saunders.)

Figure 2 Cell-mediated immunity in IBD. After luminal bacterial cell wall products lead to macrophage activation, specific antigen presentation occurs, resulting in the activation and expansion of CD4+ T helper lymphocytes. The activation of T helper cells leads to enhanced B cell proliferation and maturation, resulting in increased numbers of IgG-producing plasma cells. Resultant secretion of soluble IL-2 receptor by activated mucosal lymphocytes involved in the inflammatory process leads to increased levels of circulating soluble IL-2 receptor, which can be found to correlate with disease activity. In the normal intestine, the predominant immunoglobulin isotype secreted by B cells is IgA, which protects against pathogens by antigen exclusion. IgA overall increase in IgG-secreting lamina propria B cells has been demonstrated. In marked contrast to IgA, IgG is capable of fixing complement, arming NK cells and activating phagocytes. The increase in IgG subclasses is composed primarily of lgG1 and lgG3 in ulcerative colitis, whereas in Crohn's disease the increase is predominantly in lgG1 and lgG2. (Adapted with permission from Screiber S, Raedler A, Stenson WF and MacDermott RP (1992) The role of the mucosal immune system in inflammatory bowel disease. In: MacDermott RP and Elson CO (eds) Gastroenterology Clinics of North America, 21: 453. Philadelphia: WB Saunders.)

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