The normal intestinal mucosa: a state of ‘controlled inflammation’

The focus of investigation in inflammatory bowel disease (IBD) is almost invariably centered on the various cellular and soluble components of the mucosal immune system whose abnormal number or functions presumably underlies the pathogenesis of chronic intestinal inflammation. Although this approach is obviously justified, it is easy to lose sight of the peculiar conditions that allow the normal intestinal immune system to exert a protective rather than an aggressive role. As a matter of fact the intestinal immune system is not only the largest of the body, but primarily a biological shield functioning in unique ways that distinguish it from all other defense mechanisms. Because it is constantly exposed to the external environment, and carries an extremely rich and varied endogenous flora, the gut mucosa is adapted to work under intense, yet physiological, conditions of permanent antigenic pressure. This pressure requires and brings into action an enormous amount of organized (Peyer's patches and lymphoid follicles) and diffuse (intraepithelial lymphocytes and lamina propria mononuclear cells) lymphoid cells that respectively form the gut-associated lymphoid tissue (GALT) and the mucosaassociated lymphoid tissue (MALT) [1]. The existence of this population of mature immunocytes all along the lining of the gastrointestinal tract is quantitatively and qualitatively unparalleled in other organs, including those with a mucosal surface such as the oral cavity, the lungs and airways, the genitourinary tract, and the mammary glands. For this reason the term 'controlled' or 'physiological intestinal inflammation' has been coined to reflect the fact that activated immunocytes are present in large numbers and, rather than causing injury, afford instead an essential protection to the gut and indirectly the rest of the body. Despite its importance this terminology is seldom used outside of the realm of mucosal immunology and it is difficult to find it even in comprehensive textbooks of mucosal immunology [2]. Interestingly, the majority of components and functions involved in physiological intestinal inflammation are the same responsible for pathological inflammation as found in IBD and other conditions. Thus, the question arises of what distinguishes one from the other, and the answer is the appropriateness or not of the local defense mechanisms. There is not enough information to clearly define what constitutes an inappropriate defense response in IBD and why it endures over time, but there is a reasonably good knowledge of the components responsible for physiological intestinal inflammation (Fig. 1). Since avoiding all dietary, microbial or self stimuli that are potentially harmful is practically impossible, the intestine has devised control mechanisms that aUow it to limit the quantity and quality of the antigens presented to the mucosa and GALT. According to Fig. 1 an appropriate response resulting in physiological inflammation relies on two types of control mechanisms: physical and biological. The first depends on the intrinsic properties of the gut and epithelium, while the latter involves circulatory, humoral and immune mechanisms. Immune mechanisms rely on both innate and adaptive responses, and when specific immunity is required it can either incite a switch-on response by the induction of effector cells that eliminate the antigen (active immunity), or a switch-off" response resulting in a lack or suppression of response to the antigen (tolerance). An elaborate discussion of each component and function listed in the diagram is beyond the scope of this review, and some of these topics will be covered more comprehensively in other chapters of this book. Instead, the goal of this review is to provide the reader with an integrated overview of the components that together are presumably