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• W2003111539 abstract "The epithelia that line the vast mucosal surfaces of the gastrointestinal, respiratory, and urogenital tracts serve as delicate interfaces between external environments, rich in foreign antigens and microbial pathogens, and the internal environment of the mucosa. A major branch of the immune system operates in mucosal tissues, providing these surfaces with protective secretory antibodies (11McGhee J.R. Mestecky J. Dertzbaugh M.T. Eldridge J.H. Hirasawa M. Kiyono H. Vaccine. 1992; 10: 75-88Crossref PubMed Scopus (789) Google Scholar). Sampling of luminal antigens occurs at specialized local inductive sites (the “organized mucosa-associated lymphoid tissue” or O-MALT) that appear as single or aggregated mucosal lymphoid follicles in the tonsils, adenoids, bronchi, and intestines, including the colon and rectum. For antigens to elicit mucosal immune responses, they must be transported across the epithelial barrier at these sites. This is accomplished by induction of a specialized epithelium over mucosal lymphoid follicles (the “follicle-associated epithelium”). The follicle-associated epithelium contains M cells, a unique epithelial cell type specialized for transepithelial transport of macromolecules, particles, and microorganisms (16Neutra M.R. Pringault E. Kraehenbuhl J.-P. Annu. Rev. Immunol. 1996; 14: 275-300Crossref PubMed Scopus (394) Google Scholar). M cells are well suited for efficient endocytosis and transcytosis. They lack the rigid brush border cytoskeleton of their enterocyte neighbors, and their apical surfaces have broad membrane microdomains from which endocytosis occurs (Figure 1). The M cell basolateral membrane is deeply invaginated to form a large intraepithelial “pocket” containing T lymphocytes (including CD4+ helper cells and CD45RO+ memory cells), B lymphocytes, and macrophages (16Neutra M.R. Pringault E. Kraehenbuhl J.-P. Annu. Rev. Immunol. 1996; 14: 275-300Crossref PubMed Scopus (394) Google Scholar). This structural specialization brings the basolateral cell surface to within a few microns of the apical surface and greatly shortens the distance that transcytotic vesicles must travel to cross the epithelial barrier. Endocytic or phagocytic uptake of foreign antigens or particles is followed by rapid transcytosis directly to the intraepithelial pocket, with little or no retention in M cell lysosomes. After M cell transport, antigens are processed and presented by macrophages, dendritic cells, and B cells within and below the epithelium, resulting in generation of IgA-committed, antigen-specific B lymphoblasts that proliferate locally in the germinal centers of O-MALT and migrate via the bloodstream to distant mucosal and glandular tissues, where they differentiate into plasma cells. The dimeric or polymeric IgA antibodies thus produced are selectively bound by epithelial polymeric immunoglobulin receptors, transcytosed across epithelial cells, and released into glandular and mucosal secretions (2Apodaca G. Bomsel M. Arden J. Breitfeld P.P. Tang K.C. Mostov K.E. J. Clin. Invest. 1991; 87: 1877-1882Crossref PubMed Scopus (53) Google Scholar). Thus, M cell transcytosis is an important first step in initiation of a secretory immune response. Although some vesicles in the M cell apical cytoplasm contain the endosomal protease cathepsin E, the late endosome/lysosome membrane marker lgp120, and generate an acidic internal milieu (1Allan C.H. Mendrick D.L. Trier J.S. Gastroenterology. 1993; 104: 698-708PubMed Google Scholar), antigens and microorganisms are generally delivered intact and alive across M cells. This is consistent with our demonstration that when Peyer's patch lymphoblasts of mucosally immunized mice are used to generate hybridomas, the resulting monoclonal antibodies are primarily dimeric IgAs directed against microbial surface components. Such antibodies are well suited to intercept intact pathogens on mucosal surfaces and can be sufficient to protect against lethal doses of the corresponding pathogen (15Neutra, M.R., Michetti, P., and Kraehenbuhl, J.-P. (1994b). In Physiology of the Gastrointestinal Tract, Third Edition, L.R. Johnson, ed. (New York: Raven Press), pp. 975–1009.Google Scholar). M cell transport of enteric microorganisms seems to be a key strategy for host defense, but the molecular mechanisms involved in transport are largely unknown. For example, Vibrio cholerae in the small intestine adheres to peripheral components of the glycocalyx on microvillus tips of enterocytes but does not invade these cells; rather, the bacteria form colonies and secrete cholera toxin, which induces secretion of chloride ions by epithelial cells, causing a potentially lethal diarrhea. The interaction of V. cholerae with M cells is dramatically different: the bacterial outer membrane and the M cell apical membrane adhere closely via an unidentified receptor–ligand interaction, inducing recruitment of M cell actin filaments (14Neutra, M.R., Giannasca, P.J., Giannasca, K.T., and Kraehenbuhl, J.-P. (1994a). In Infections of the GI Tract, M. Blaser, P.D. Smith, J.I. Ravdin, H.B. Greenberg, and R.L. Guerrant, eds. (New York: Raven Press), pp. 163–178.Google Scholar), phagocytosis, release into the intraepithelial pocket and subepithelial spaces, and phagocytosis of Vibrios by macrophages (Figure 2A). Digestion and antigen presentation in Peyer's patches result in secretion of IgA antibodies that can be sufficient to clear the infection and prevent subsequent V. cholerae colonization and diarrheal disease. Certain pathogenic strains of Escherichia coli also colonize the mucosa and interact with M cells. For example, the rabbit pathogenic E. coli RDEC-1 and the human enteropathogenic E. coli EPEC initially associate with peripheral components of the M cell surface and then induce the formation of stable “pedestals” supported by submembrane actin assemblies (Figure 2A). Studies of the interaction of EPEC with cultured epithelial cell types have shown that initial attachment induces tyrosine phosphorylation of local host cell membrane proteins at the attachment site, and these in turn interact with the bacterial protein intimin (homologous to Yersinia invasins), which mediates intimate attachment and is required for reorganization of the local actin cytoskeleton (19Rosenshine I. Ruschkowski S. Stein M. Reinscheid D.J. Mills S.D. Finlay B.B. EMBO J. 1996; 11: 3551-3560Google Scholar). EPEC has developed this elaborate strategy to maintain surface colonization of enterocytes, but the same molecular machinery seems to operate on M cells. Several pathogenic bacteria exploit the M cell transport mechanism to infect mucosal tissues and/or to spread systemically before they can be halted by an immune response. However, M cells represent only a tiny minority in the intestinal epithelium. How do bacteria recognize and adhere to these rare cells? Target cell selectivity by bacteria is generally based on the presence of specific host cell surface oligosaccharide epitopes that are exploited as receptors by lectin-like bacterial adhesins (8Hultgren S.J. Abraham S. Caparon M. Falk P. St. Geme III, J.W. Normark S. Cell. 1993; 73: 887-901Abstract Full Text PDF PubMed Scopus (338) Google Scholar). Several groups have shown that M cell glycosylation patterns are distinct from those of enterocytes, although the membrane glycoconjugates of M cells vary in different intestinal regions, in different species, and even among different mouse strains (14Neutra, M.R., Giannasca, P.J., Giannasca, K.T., and Kraehenbuhl, J.-P. (1994a). In Infections of the GI Tract, M. Blaser, P.D. Smith, J.I. Ravdin, H.B. Greenberg, and R.L. Guerrant, eds. (New York: Raven Press), pp. 163–178.Google Scholar). Furthermore, there are variations in the glycosylation patterns of individual M cells within a single follicle-associated epithelium. This diversity may determine the tropisms of pathogens that exploit M cells for invasion and might allow the M cells to “sample” a wide variety of microorganisms. Bacterial pathogens that adhere to M cell surfaces can initiate epithelial signal transduction events that promote internalization. For example, Salmonella typhi and typhimurium adhere rapidly and selectively to M cells (9Jones B.D. Ghori N. Falkow S. J. Exp. Med. 1994; 180: 15-23Crossref PubMed Scopus (681) Google Scholar), apparently via novel lectin-like fimbriae (3Baumler A.J. Tsolis R.M. Heffron F. Proc. Natl. Acad. Sci. USA. 1996; 93: 279-283Crossref PubMed Scopus (206) Google Scholar). The corresponding M cell surface receptors have not been identified, although our recent studies on Caco-2 cells in vitro have identified a candidate gal-galNAc epitope that is recognized by S. typhimurium. Adherence of S. typhimurium to M cells induces rapid disassembly of the apical cytoskeleton and loss of microvilli, ruffling and “ballooning” of the M cell apical surface, and engulfment of bacteria by “macropinocytosis” (Figure 2B). Studies utilizing intestinal cell lines in vitro have shown that attachment and entry of Salmonella is accompanied by activation of intracellular signaling pathways and local cytoplasmic Ca2+ spikes (4Bliska J.B. Galan J.E. Falkow S. Cell. 1993; 73: 903-920Abstract Full Text PDF PubMed Scopus (279) Google Scholar), and presumably, similar molecular events occur in M cells. Shigella infection results in severe damage of the intestinal and colonic mucosa and loss of epithelial barrier function. Shigella uses a remarkable mechanism to spread from cell to cell: the bacterium adheres to the plasma membrane and undergoes phagocytosis and then disrupts the phagosome membrane to enter the cytoplasm, where it proliferates and induces assembly of a “tail” of actin filaments that propels the bacteria into a cytoplasmic process that is phagocytosed by the neighboring cell, thus repeating the cycle of infection (20Sansonetti P.J. Rev. Infect. Dis. 1991; 13: 285-292Crossref Scopus (97) Google Scholar). Although Shigella initially gains entry through the intestinal epithelium in vivo, it is unable to invade via the apical surfaces of cultured enterocyte monolayers and can infect only via basolateral membranes. This paradox was resolved by the observation that pathogenic strains of Shigella are selectively transcytosed by M cells; this is followed by local invasion of adjacent epithelial cells via basolateral cell surfaces, rapid influx of neutrophils and macrophages, and cytokine-mediated disruption of the epithelial barrier (18Perdomo J.J. Cavaillon J.M. Huerre M. others J. Exp. Med. 1994; 180: 1307-1319Crossref PubMed Scopus (243) Google Scholar; Figure 2C). Viruses exploit the fact that M cells will endocytose and transport any small particles that adhere to their surfaces. M cell–specific adherence is a strategy used by the mouse pathogen, reovirus, to gain access to its target cells in the mucosa (Figure 2D). Reovirus is transmitted orally and, although it is partially digested by proteases in the intestinal lumen, this does not inactivate the virus; rather, it remodels the viral outer capsid and induces extension of the viral hemagglutinin σ1, creating highly infectious “intermediate subviral particles” (17Nibert M.L. Furlong D.B. Fields B.N. J. Clin. Invest. 1991; 88: 727-734Crossref PubMed Scopus (64) Google Scholar). Indeed, proteolytic conversion to intermediate subviral particles is a prerequisite for M cell adherence (14Neutra, M.R., Giannasca, P.J., Giannasca, K.T., and Kraehenbuhl, J.-P. (1994a). In Infections of the GI Tract, M. Blaser, P.D. Smith, J.I. Ravdin, H.B. Greenberg, and R.L. Guerrant, eds. (New York: Raven Press), pp. 163–178.Google Scholar), and this suggests that extension of the σ1 protein may be required to allow contact with as yet unidentified M cell apical receptors. Poliovirus in humans also enters the body by the oral route and proliferates in Peyer's patches before spreading to target neurons. Poliovirus type-1 and the attenuated Sabin strain have been shown to adhere selectively to human M cells and to be taken up in clathrin-coated vesicles. This explains the effectiveness of live, attenuated poliovirus as an oral vaccine that prevents infection of wild-type virus via mucosal surfaces. The receptor for poliovirus on neuronal target cell membranes has been identified as a member of the immunoglobulin superfamily, and the cloned gene has been used to create transgenic mice that can be infected by injection of virus. Such mice are not infected when challenged orally; apparently, the virus uses a different receptor on M cells. Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) can enter the body through intact mucosal surfaces. Studies of SIV transmission in monkeys have established that SIV infection may occur across the stratified vaginal epithelium where M cells are absent, apparently via intraepithelial CD4+ dendritic cells (13Miller C. Vogel P. Alexander N.J. Sutjipto S. Hendrickx A.G. Marx P.A. Am. J. Pathol. 1992; 141: 655-660PubMed Google Scholar), but the mechanisms of rectal mucosal entry are not clear. Intestinal epithelial cells do not express the gp120 receptor CD4, but their membranes do contain the alternate glycolipid receptor galactosylceramide. This has led to the suggestion that HIV particles could adhere to glycolipid receptors on rectal enterocytes and be endocytosed, to infect the epithelium or to be transported to underlying target cells. But would viral particles have access to galactosylceramide on epithelial cell apical surfaces in vivo? Apical surfaces of enterocytes consist of rigid, closely-packed microvilli coated by transmembrane mucin-like glycoproteins that form a continuous, 400–500 nm thick blanket called the “filamentous brush border glycocalyx” (10Maury J. Nicoletti C. Guzzo-Chambraud L. Maroux S. Eur. J. Biochem. 1995; 228: 323-331Crossref PubMed Scopus (62) Google Scholar), but M cells generally lack this diffusion barrier (Figure 3). To evaluate the effect of the thick enterocyte filamentous brush border glycocalyx and the thin M cell glycocalyx on access of virus- or bacteria-sized particles to glycolipid receptors, we tested the ability of a specific ligand, the nontoxic, pentameric binding (B) subunit of cholera toxin (CTB), to bind to its glycolipid receptor, ganglioside GM1, on M cells and enterocytes (7Frey A. Giannasca K.T. Richard-Weltzin R. Giannasca P.J. Reggio H. Lencer W.I. Neutra M.R. J. Exp. Med., in press. 1996; Google Scholar). Soluble CTB (diameter, 6.4 nm) can bind to GM1 on all intestinal epithelial cells, but to do so it must come into very close contact with the membrane, because the carbohydrate head groups of GM1 protrude only 2.5 nm above the surface of the lipid bilayer. Using colloidal gold and latex particles coated with CTB, we showed that the filamentous brush border glycocalyx excluded particles as small as 28 nm in diameter and as large as 1.1 μm from contact with membrane glycolipids, whereas the M cell glycocalyx allowed close contact, adherence, and endocytosis of 28 nm CTB probe but not bacteria-sized, CTB-coated particles (7Frey A. Giannasca K.T. Richard-Weltzin R. Giannasca P.J. Reggio H. Lencer W.I. Neutra M.R. J. Exp. Med., in press. 1996; Google Scholar). This is consistent with our previous observation that HIV failed to penetrate the filamentous brush border glycocalyx of rabbit or mouse enterocytes, did not contact enterocyte plasma membranes, and was not taken up by these cells but did adhere to rabbit and mouse M cells and was transcytosed (14Neutra, M.R., Giannasca, P.J., Giannasca, K.T., and Kraehenbuhl, J.-P. (1994a). In Infections of the GI Tract, M. Blaser, P.D. Smith, J.I. Ravdin, H.B. Greenberg, and R.L. Guerrant, eds. (New York: Raven Press), pp. 163–178.Google Scholar). Since M cells are numerous in human rectum, it seems possible that the accessibility and high endocytic activity of M cell surfaces could provide a transcytotic mechanism for infection of mucosal CD4+ T cells, macrophages, and dendritic cells. Understanding the basis for selective M cell transport could be of great importance for the rational design of mucosal vaccination strategies. M cell targeting of nonliving vaccines has proven difficult because unprotected macromolecules are readily digested in the intestine, and there is little information available concerning the apical membrane components on M cells that might serve as potential receptors. One approach has been to package antigens in microparticles that provide protection from intestinal enzymes and take advantage of the fact that M cells can endocytose particles up to several μm in diameter, while enterocytes cannot (6Eldridge J.H. Staas J.K. Meulbroek J.A. McGhee J.R. Tice T.R. Gilley R.M. Mol. Immunol. 1991; 28: 287-294Crossref PubMed Scopus (372) Google Scholar). Microparticles and liposomes can adhere to mucosal surfaces by hydrophobic interactions, but uptake by M cells is inefficient because they are readily entrapped in mucous gels and many fail to reach the mucosa. Macromolecules or particles can be conjugated or coated with a ligand, such as CTB, that allows passage through mucous gels and adherence to M cells, but then accessibility to membrane receptors is a limiting factor (7Frey A. Giannasca K.T. Richard-Weltzin R. Giannasca P.J. Reggio H. Lencer W.I. Neutra M.R. J. Exp. Med., in press. 1996; Google Scholar). These difficulties have been bypassed by exploiting the pathogens that target themselves to M cells and enter the mucosa at inductive sites. Live, attenuated strains of V. cholerae, S. typhi, and poliovirus are now established as safe, effective oral vaccines, and genetically engineered strains of these microorganisms have been designed that carry and/or express genes for heterologous antigens (12Mekalanos, J.J. (1992). In Genetically Engineered Vaccines (Adv. Exper. Med. Biol.), J.E. Ciardi, J.R. McGhee, and J.M. Kieth, eds. (New York: Plenum Press), pp. 43–50.Google Scholar). However, the biology of these live vectors introduces new challenges. For example, V. cholerae vaccine strains that lack toxin genes can still cause diarrhea, apparently because epithelial cells release cytokines simply in response to bacterial adherence (12Mekalanos, J.J. (1992). In Genetically Engineered Vaccines (Adv. Exper. Med. Biol.), J.E. Ciardi, J.R. McGhee, and J.M. Kieth, eds. (New York: Plenum Press), pp. 43–50.Google Scholar). A major challenge in the use of genetically engineered S. typhi and typhimurium vaccine strains is that of achieving sufficient attenuation to ensure safety while preserving sufficient M cell adherence and proliferation in mucosal cells to provide immunity. Attenuated Shigella strains that are transcytosed by M cells but lack the ability to subvert the host cell cytoskeletal machinery for cell–cell spread have been designed (20Sansonetti P.J. Rev. Infect. Dis. 1991; 13: 285-292Crossref Scopus (97) Google Scholar), but local release of cytokines and chemotactic factors in response to Shigella entry might cause breakdown of normal epithelial barrier function. The poliovirus genome has severe size constraints, but novel strategies have recently been developed that allow live recombinant poliovirus to serve as a vaccine vector for delivery of foreign antigens (5Choi W.S. Pal-Ghosh R. Morrow C.D. J. Virol. 1991; 65: 2875-2883PubMed Google Scholar). M cell transport is an important factor in induction of mucosal immune responses and is exploited by pathogenic microorganisms for invasion of the intestinal mucosa. The specific molecular recognition systems and nonspecific adherence mechanisms that determine the efficiency of the M cell transport pathway are largely unknown. Future studies on the interactions of micoorganisms with this highly specialized epithelial cell will enhance our understanding of microbial pathogenesis and will lead to more effective strategies for targeting of vaccines and live microbial vaccine vectors to the mucosal immune system." @default.
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• W2003111539 title "Epithelial M Cells: Gateways for Mucosal Infection and Immunization" @default.
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