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Chapter category: Immunology

Induction of Tolerogenic versus Pathogenic Mucosal Immune Responses by Commensal Enteric Bacteria

Chapter authors:
Dirk Haller and R. Balfour Sartor

Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) are spontaneously relapsing, immunologically-mediated disorders of the gastrointestinal tract. Microbial agents are intimately involved in each of the four major current etiologic theories of these idiopathic disorders (Table 1). Rapidly evolving studies in experimental rodent models of chronic, immune-mediated intestinal inflammation illustrate the critical importance of host genetic susceptibility in determining the aggressiveness and chronicity of inflammation. A characteristic feature of the mucosal immune system in the normal host is that protective cell-mediated and humoral immune responses against invading pathogens are allowed to proceed while pathogenic responses to ubiquitous bacterial antigens of the indigenous intestinal microflora are prevented. Under normal circumstances detrimental inflammatory responses to phlogistic luminal contents are prevented by several mechanisms including exclusion of bacterial antigens or macromolecules by a viscous mucus layer, an intact epithelial barrier, secreted antibodies, regulatory T lymphocytes which mediate tolerance, immunosuppressive mediators, as well as intestinal epithelial cells and lamina propria macrophages which are relatively refractory to luminal stimulants. Episodic breaks in the mucosal barrier due to transient infections or luminal toxins occur frequently, challenging the mucosal immune system with bacterial components. Homeostasis (tolerance) versus chronic intestinal inflammation is determined by either a regulated or an uncontrolled response of the host, respectively, to the constant antigenic drive of its resident flora. These responses are genetically determined. In genetically susceptible hosts, the lack of appropriate mechanisms to downregulate mucosal immune responses (loss of immunologic tolerance) and an ineffective mucosal barrier function results in continuous stimulation of the mucosal immune system with chronic inflammation as a the consequence. In this Chapter, we will discuss immunological and bacterial mechanisms which mediate tolerance and inflammation in response to resident enteric bacteria in experimental animals, with selected clinical examples documenting relevance to IBD.

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