Escherichia coli and the mucosal immune system

The meeting was held in the beautiful city of Ghent, Belgium, to bring together basic scientists and clinicians working on Escherichia coli and the mucosal immune system; in particular focusing on cellular interactions, immune modulation and vaccination strategies in humans and animals. The aim was to exchange knowledge on the pathogenicity of different types of E. coli and recent advances in the area of mucosal immunity. The meeting was timely given the recent outbreak in northern Germany of an emergent Shiga toxigenic E. coli strain that was associated with the deaths of over 45 people and caused hemolytic uremic syndrome in nearly 800 individuals according to the European Centre for Disease Prevention and Control.     

The intestinal epithelial cell: processing and presentation of antigen to the mucosal immune system

Summary: The immunologic tone of the intestinal tract is one of suppressed or highly regulated responses. While there arc several components (intrinsic and extrinsic to the gut-associated lymphoid tissue) responsible for this immunologically suppressed tone, the intestinal epithelial call (IEC) has been proposed as a key player in this process, IECs can take up and process antigen but distinct surface molecules and restriction elements allow them to present these antigens to unique regulatory T tells. These include the expression of the class II molecule CD I d as well as a novel CD8 ligand, gp180. These molecules come together to activate a subpopulation of CD8⁺ regulatory cells whose function is to suppress immune responses in an antigen non-specific fashion most likely through cognate interactions. This form of regulation may be unique to the gut-associated lymphoid tissue which is consistent with the unsual demands upon this part of the immune system.     

Antigen processing and presentation.

An overview of the various aspects of antigen degradation and presentation is given with special emphasis on the possible occurrence of variation in the enzymatic machinery present in different cells or individuals. Different procedures for epitope mapping are also presented as well as the characterization of universal epitopes in humans. The latter finding is of considerable importance for the development of subunit vaccines. Finally, the structure of T cell epitopes is discussed.     

Chemokine receptors and leukocyte trafficking in the mucosal immune system

The CC chemokine receptors CCR6, CCR9, and CCR10 all contribute to the positioning of leukocytes at mucosal locations. Mucosal epithelial cells are major sources of the chemokine ligands for each of these receptors, although the pattern of expression of the individual ligands differs at distinct mucosal sites. CCR6 is expressed by most B cells, subsets of CD4 and CD8 memory T cells, and subsets of dendritic cells (DCs). Absence of CCR6 in mice leads to abnormal expansion of intestinal intraepithelial T cells and lamina propria T cells, smaller Peyer's patches, and defects in IgA-mediated responses to oral antigens and pathogens. CCR9 is present on thymocytes, most intestinal intraepithelial lymphocytes, and other types of intestine-homing T cells. CCR 10 is found on skin-homing T cells and also direct IgA-producing plasma cells into mucosal sites. This review discusses the role of these chemokine receptors in homeostatic regulation of the mucosal immune system.     

Regulation of IgA B-cell development in the mucosal immune system

The factors regulating the differentiation of IgA B cells have been of great interest to mucosal immunologists as well as those generally interested in B-cell differentiation. It is now clear that such differentiation involves two major steps: first, isotype switch differentiation of surface IgM-bearing B cells into surface IgA-bearing B cells and, second, terminal differentiation of IgA B cells into IgA-producing plasma cells. Both of these steps are regulated processes that are under the influence of various cytokines and lymphokines. This paper presents data that define the role of cytokines and lymphokines in the regulation of IgA B-cell differentiation. A model of IgA B-cell differentiation is described in which the first step involves activation of the C alpha gene, while the latter is in germline configuration and thus the induction of surface IgM-bearing B cells partially committed to IgA expression. This occurs in Peyer's patches as a result of as yet incompletely defined signals from patch “switch cells.” The second step consists of conversion of the partially committed B cells to fully IgA-committed B cells and thus the completion of isotype switch differentiation. This step may be under the control of interleukin-4 (IL-4). The last step of the model involves the activation of IgA B cells (by antigen or mitogen) followed by the appearance on the cell surface of receptors which allow the cell to interact with cytokines or lymphokines (particularly IL-5). Such interaction results in cells capable of secreting IgA. Evidence is presented that an important adjuvant for mucosal immune responses, cholera toxin, acts to augment IgA production by promoting IgA B-cell differentiation at the isotype switch step.     

Mucosal defense mechanism in health and disease. Role of the mucosal immune system.

The mucosal immune system is characterized predominantly by the secretory antibody response and gut-associated lymphoid tissue, cellular part of the mucosal immune system. The secretory antibody system depends on local production and selective epithelial transport of secretory IgA and IgM. Furthermore, secretory antibodies and interactions between the intestinal epithelium and T cells are involved in the mucosal down-regulation of the systemic immune system. Neuropeptides play a crucial role in the regulation of mucosal immune responses. It is possible that impairment of the mucosal immune response contributes to the pathogenesis of various intestinal diseases, such as inflammatory bowel disease. Until recently, however, mucosal immunity received relatively little attention from both basic and clinical scientists. Further research on mucosal immunity seems to have promise in helping to provide new understanding of the immune mechanisms and pathogenesis of several gastrointestinal and systemic diseases.     

Interaction of mucosal microbiota with the innate immune system

Organisms live in continuos interaction with their environment; this interaction is of vital importance but at the same time can be life threatening. The largest and most important interface between the organism and its environment is represented by surfaces covered with epithelial cells. Of these surfaces, mucosae comprise in humans approximately 300 m2, and the skin covers approximately 1.8 m2 surface of the human body. Mucosal tissues contain two effector arms of the immune system, innate and adaptive, which operate in synergy. Interaction with commensal bacteria, which outnumber the nucleated cells of our body, occurs physiologically on epithelial surfaces; this interaction could pose the risk of inflammation. The mucosal immune system has developed a complex network of regulatory signalling cascades that is a prerequisite for proper activation but also for a timely inactivation of the pathway. As demonstrated in gnotobiotic animal models of human diseases, impaired regulation of mucosal responses to commensal bacteria plays an important role in the development of several inflammatory and autoimmune diseases.     

Immunological functions of the gut--role of the mucosal immune system

This review summarizes recent information about immune responses in the intestinal mucosa with emphasis on the role of orally-administered antigens from the external environment. The intestinal mucosa provides an extensive surface for potential absorption of pathogenic environmental antigens, such as microbes, chemicals, and food. The intestinal mucosa is densely populated by IgA-producing plasma cells. The humoral immune responses to antigens in the intestinal mucosa are largely of the IgA class in secretory form (sIgA). This sIgA provides an immunological barrier to absorption of antigens on the mucosal epithelium and to penetration into the body. The cell-mediated immune mechanism is also equipped in the mucosal sites. In addition, the mucosal immune response induces hyporesponsiveness of nonmucosal (systemic) immune reactions, and the liver is an integral part of the mucosal immune system. Thus we consider that the mucosal immune system plays a central role in the maintenance of the homeostasis of the total immune system.     

Dynamic regulation of innate lymphoid cells in the mucosal immune system

The mucosal immune system is considered a local immune system, a term that implies regional restriction. Mucosal tissues are continually exposed to a wide range of antigens. The regulation of mucosal immune cells is tightly associated with the progression of mucosal diseases. Innate lymphoid cells (ILCs) are abundant in mucosal barriers and serve as first-line defenses against pathogens. The subtype changes and translocation of ILCs are accompanied by the pathologic processes of mucosal diseases. Here, we review the plasticity and circulation of ILCs in the mucosal immune system under physiological and pathological conditions. We also discuss the signaling pathways involved in dynamic ILC changes and the related targets in mucosal diseases.     

The mucosal immune system and HIV-1 infection

Recent progress in HIV-1 and SIV pathogenesis has revealed that mucosal tissues, primarily the gastrointestinal tract, are major sites for early viral replication and CD4+ T-cell destruction, and may be the major viral reservoir, even in patients receiving HAART. This is likely attributable to the fact that the majority of mucosal CD4+ T-cells co-expressing chemokine receptors requited for HIV-1 entry, reside in mucosal tissues. Furthermore, the intestinal mucosal immune system is continuously bombarded by dietary antigens, resulting in continual lymphocyte activation, dissemination, and homing of these activated lymphocytes (including CCR5+CD4+ T-cells) throughout mucosal tissues. Thus, the intestinal immune system represents a very large target for HIV-infection, which is continually generating newly activated CD4+ T-cells that are the preferred target of infection. Thus, HIV-1 appears uniquely adapted to persist and thrive in the mucosal-tissue environment. The selective loss of intestinal CD4+ T-cells from immune-effector sites is also likely to explain, at least in part, the preponderance of opportunistic infections at mucosal sites. It is increasingly evident that effective therapies and vaccines must be directed towards eliminating HIV-1 in mucosal tissue reservoirs, protecting mucosal CD4+ T-cells and stimulating effective mucosal immune responses.