Inflammatory Bowel Disease: From Bench to Bedside

Abstract

The immunologic and antigenic challenge faced along the gastrointestinal tract is truly extraordinary. Across a surface area that approximates a tennis court, it is here that we separate the highest concentration of foreign antigen (mostly food and bacteria) from the largest complement of lymphocytes in the body by a single cell layer of polarized epithelium. The gut-associated lymphoid tissue (or GALT) has evolved highly complex mechanisms to permit life in this 'open ecosystem'. Although the dominant 'response' of the GALT to orally administered antigen or non-invasive microbes is that of immunologic tolerance (or oral tolerance), the GALT can also initiate both regional and systemic responses to certain antigens and pathogens. The precise molecular mechanisms by which the mucosal immune system regulates this intricate balance between tolerance and responsiveness remain incompletely understood [1, 2]. While most individuals can maintain 'homeostasis' and health in the face of this extreme immunologic challenge, others cannot. Indeed, the clinical entities collectively known as inflammatory bowel disease, or IBD (i.e. Crohn's disease and ulcerative colitis) are conditions in which inflammation persists at various anatomic sites along the gastrointestinal tract [3]. IBD is the second most common disease of potential autoimmune etiology in the United States - affecting approximately 1 in 2 to 1 in 10 individuals [4]. Although many details regarding the etiology of IBD remain unclear, a central hypothesis has emerged. Specifically, IBD can be said to represent an aberrant immune response to bacteria from the lumen of the intestinal tract in a subset of individuals with a genetic predispostion or propensity to develop chronic, mucosal inflammation. This is a broad hypothesis that needs to be viewed within the context of the current genetic data describing the marked heterogeneity of human IBD. Still, the microbial focus inherent to the hypothesis highlights a series of important cell types at the mucosal interface (T lymphocytes and antigen-presenting cells including intestinal epithelial cells) and their associated questions. For example, what is the nature of the bacterial species that are responsible? Do the predisposing genes relate to immunologic function within the GALT or to intrinsic properties of the gastrointestinal tract (e.g. intestinal barrier function)? What are the immune effector cells that mediate IBD and how are they modulated by bacteria? In this chapter we address these and other questions and early events relevant to the central hypothesis outlined; in particular, those involving interaction between bacteria and the lymphocytes of the GALT at the epithelial interface. © 2005 Springer Science+Business Media, Inc.