Bacterial enterotoxins: multiple effects in the modulation of ...


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Bacterial enterotoxins: multiple effects in the modulation of ...

  1. 1. Norwegian Society of Immunology and the Faculty of Medicine, University of Oslo September 5, 2002, 3:15-5:00 PM For location, see NSI website: MUCOSAL IMMUNOLOGY Michael W. Russell Depts. of Microbiol. and Oral Biol., Witebsky Center for Microbial Pathogenesis and Immunology, Univ. at Buffalo (SUNY), Buffalo, NY Bacterial enterotoxins and the modulation of mucosal immune responses Given that the great majority (>80%) of human infectious diseases either directly afflict or invade through the mucosae, it would seem that strategies of immunization designed to elicit immune responses at these surfaces would be optimal for protection against infections. However, the default mode of response within the mucosal immune system, especially to innocuous materials such as food antigens, inhaled dust, and commensal microorganisms, is one of tolerance. Developing an effective mucosal immune response depends on “danger” signals induced, for example, by aggressive pathogens or their toxins. The heat-labile enterotoxins produced by Vibrio cholerae or Escherichia coli are not only exceptionally potent mucosal immunogens, but they also have adjuvant properties that can be exploited to enhance responses to other coadministered antigens. Moreover, their nontoxic binding B subunits can serve as carriers to deliver coupled antigens to mucosal immune inductive sites. The mechanisms by which these effects are exerted are complex and multiple, acting on several cells and processes in the immune response. Data will be presented showing how heat-labile enterotoxins modulate the expression of receptors and thereby influence interactions between antigen-presenting cells and T cells, and how different enterotoxins with different binding properties exert different effects. Per Brandtzaeg LIIPAT, Inst. of Pathology, Univ. of Oslo, Rikshospitalet, Oslo Role of secretory antibodies in defence against infections The mucosal surface area of an adult individual amounts to some 400 m2. This extensive and generally quite vulnerable epithelial barrier is protected by numerous innate defence mechanisms that cooperate intimately with a local adaptive immune system. Its most prominent feature is an abundance of subepithelial plasma cells and B-cell blasts (collectively called immunocytes), constituting at least 80% of all antibody-forming cells of the body. These local immunocytes produce mainly dimeric IgA (dIgA) with incorporated J chain. A transmembrane epithelial glycoprotein called the secretory component (SC), or the polymeric Ig receptor (pIgR), is quantitatively the most important receptor of the immune system because it is responsible for external transport of large amounts of locally produced dIgA and pentameric IgM to provide secretory antibodies performing immune exclusion. Our recent construction of pIgR/SC knockout mice has substantiated the importance of secretory immunity for mucosal homeostasis and defence against early microbial colonization as well as toxin-producing pathogens. Data from collaborative studies with murine infection models will be presented.