C. G. M. Gahan, University College Cork, Ireland
The human gastrointestinal tract represents a complex anatomical site with an enormous surface area (400 m2) in which the external environment comes into contact with the host. This region is highly specialised in order to permit adsorption of nutrients from food whilst preventing penetration by pathogens and toxic agents. The lumen of the GI tract also represents an extremely complex microbial ecosystem in which 300-500 different bacterial species compete to reach levels of approximately 1011 CFU/g faeces (Simon and Gorbach, 1984). This ecological diversity is further highlighted by recent molecular studies that demonstrate a vast array of unculturable microorganisms in the human GI tract (Eckburg et al., 2005). In order to monitor the GI tract for pathogens and to prevent inappropriate responses to the commensal flora and potential allergens, higher mammals have evolved a complex local immune network that covers the entire GI tract and interacts with the systemic immune and neuronal systems. In humans, this gastrointestinal immune system is thought to make up approximately 70% of the total immune system.
In the response to pathogens, it is clear that the cellular localisation and nature of the pathogenic agent are important factors that influence the ensuing immune response. Epithelial cells, dendritic cells and macrophages coordinate the early immune response through recognition of microbe-associated molecular patterns (MAMPs) (Niedergang et al., 2004) such as lipopolysaccharide (LPS), flagellin and CpG DNA. This priming of the immune response induces chemo-kines such as IL-8 and CCL20/MIP-3a that serve to recruit inflammatory phagocytes and dendritic cells to the site of infection. Dendritic cells and other professional antigen presenting cells then migrate to local immune centres to present antigen to T and B lymphocytes. Production of specific mucosal antibody (slgA or slgM) by plasma cells is key to the removal of extracellular pathogens such as Vibrio cholerae and Giardia lamblia from the lumen of the intestine. Intracellular pathogens including Listeria monocytogenes, Salmonella enterica serovar Typhimurium and Shigella spp. are eliminated following induction of a TH1 cell-mediated immune response in which cytokines such as interferon gamma (IFN-7) prime phagocytes to kill internalised pathogens and cytolytic CD8+ T cells specifically target infected host cells. In contrast, the response to parasitic nematodes including Trichinella and Nippostrongylus spp. requires the production of IL-4 and IL-13, cytokines that define a 1h2 response. These diverse responses are in turn influenced by the presence of the gastrointestinal flora and are modulated by virulence factors produced by microbial pathogens during pathogenesis.
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