Abstract
The gastrointestinal immune system has evolved under the dual evolutionary pressure of preventing bacterial invasion along its extensive epithelial surfaces, while permitting absorption of nutrients. Accordingly, the development, selection and function of mucosal immune cells differ from comparable characteristics of lymphoid cells in other peripheral tissues. In the normal state, intestinal immune responses are aiming at exclusion of antigens - that is, preventing translocation of intestinal microorganisms and dangerous immunogenic substances such as bacterial toxins into the lamina propria. Furthermore, presentation of soluble food proteins and components of the autologous intestinal microflora to mucosal T and B cells, apparently results in immunological downregulation as well as active suppression of systemic immune responses, a phenomenon termed mucosal or 'oral' tolerance. The normal microbial flora has a major impact on the pool size, composition, antigen recognition repertoire, and effector function of mucosal immune cells. Local antibody responses are characterized by differentiation of B lymphocytes to lamina propria plasma cells which produce polymeric immunoglobulins, a process strictly regulated by mucosal T cells. Polymeric immunoglobulins (e.g., dimeric IgA and pentameric IgM) are actively transported by a specific receptor across the epithelial barrier into the gut lumen where they can bind bacteria and soluble antigens, thereby preventing them from adhering to, and penetrating, the mucosal surface. A major population of intestinal T cells is located in the surface epithelium, thus being strategically situated at the interface between the gut lumen and the interior of the body. However, their precise role in microbial defence has not yet been established. It is remarkable how the immune system normally maintains the balance between exclusion of (but coexistence with) the commensal gut bacteria, while protecting against (and eventually eliminating) intestinal pathogens. This immune balance appears to be tightly regulated by intestinal T cells. Recent findings in various genetically manipulated mouse models suggest that a dysregulated T-cell response against the normal intestinal microflora may lead to progressive inflammatory disease in the gut. This adverse development appears to reflect abrogation of oral tolerance and may be a central mechanism in the pathogenesis of inflammatory bowel disease. Also the development of atopic allergy appears to be influenced by immunoregulatory mechanisms on which the intestinal microflora exerts a substantial impact in terms of both mucosal barrier maintenance, oral tolerance and a balanced cytokine profile.