AUTOIMMUNITY, IMMUNODEFICIENCY AND MUCOSAL INFECTIONS - CHRONIC INTESTINAL INFLAMMATION AS A SENSITIVE INDICATOR OF IMMUNOREGULATORY DEFECTS IN RESPONSE TO NORMAL LUMINAL MICROFLORA

Despite the fact that target antigens and the genetic basis of several autoimmune diseases are now better understood, the initial events lea ding to a loss of tolerance towards self-components remain unknown. On e of the most attractive explanations for autoimmune phenomena involve s various infections as possible natural events capable of initiating the process in genetically predisposed individuals. The most accepted explanation of how infection causes autoimmunity is based on the conce pt of ''molecular mimicry'' (similarity between the epitopes of an aut oantigen and the epitopes in the environmental antigen). Infectious st imuli may also participate in the development of autoimmunity by induc ing an increased expression of stress proteins (hsp), chaperones and t ransplantation antigens, which leads to abnormal processing and presen tation of self antigens. Superantigens are considered to be one of the most effective bacterial components to induce inflammatory reactions and to take part in the development and course of autoimmune mechanism s. It has long been known that defects in the host defense mechanism r ender the individual susceptible to infections caused by certain micro organisms. Impaired exclusion of microbial antigens can lead to chroni c immunological activation which can affect the tolerance to self comp onents. Defects in certain components of the immune system are associa ted with a higher risk of a development of autoimmune disease. The use of animal models for the studies of human diseases with immunological pathogenesis has provided new insights into the influence of immunore gulatory factors and the lymphocyte subsets involved in the developmen t of disease. One of the most striking conclusion arising from work wi th genetically engineered immunodeficient mouse models is the existenc e of a high level of redundancy of the components of the immune system . However, when genes encoding molecules involved in T cell immunoregu latory functions are deleted, spontaneous chronic inflammation of the gut mucosa (similar to human inflammatory bowel disease) develops. Sur prisingly, when such immunocompromised animals were placed into germfr ee environment, intestinal inflammation did not develop. Impairment of the mucosal immune response to the normal bacterial nora has been pro posed to play a crucial role in the pathogenesis of chronic intestinal inflammation. The use of immunodeficient models colonized with define d microflora for the analysis of immune reactivity will shed light on the mode of action of different immunologically important molecules re sponsible for the delicate balance between luminal commensals, nonspec ific and specific components of the mucosal immune system.