Abstract
In the human gut mucosa, specialized M cells deliver intact foreign macromolecules and commensal bacteria from the lumen to organized mucosal lymphoid tissues triggering immune responses. M cells are also major sites of adhesion and invasion for enteric pathogens. The molecular features of M cell apical surfaces that promote microbial normal attachment are still largely unknown. We have demonstrated previously that in the human colonic epithelium, carcinoembryonic antigen (CEA) and CEA-related cell adhesion molecule 1 (CEACAM1) are integral components of the apical glycocalyx which participate in epithelial–microbial interactions. In this study, based on the reactivity of specific monoclonal antibodies and on immunoelectron microscopy, we show that M cells of human colonic solitary lymphoid follicles express CEA and CEACAM1 on the apical surface. Recently these highly glycosylated molecules have been characterized as protein receptors for different bacteria. This leads us to propose a role for CEA and CEACAM1 in the adherence of enteric bacteria to the apical membrane of colonic M cells. We also hypothesize that, unlike colonic enterocytes, M cells lack the defense mechanism that eliminates CEA and CEACAM1 upon microbial binding and which is based on vesiculation of microvillus plasma membrane.
Similar content being viewed by others
References
Baranov V, Yeung MM-W, Hammarstrom S (1994) Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies. Cancer Res 54:3305–3314
Beauchemin N, Draber P, Dveksler G, Gold P, Gray-Owen S, Grunert F, Hammarstrom S, Holmes KV, Karlsson A, Kuroki M, Lin S-H, Lucka L, Najjar SM, Neumaier M, Obrink B, Shively JE, Skubitz KM, Stanners CP, Thomas P, Thompson JA, Virji M, von Kleist S, Wagener C, Watts S, Zimmermann W (1999) Redefined nomenclature for members of the carcinoembryonic antigen family. Exp Cell Res 252:243–249
Bos MP, Grunert F, Belland RJ (1997) Differential recognition of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infect Immun 65:2353–2361
Bos MP, Hogan D, Belland RJ (1999) Homologue scanning mutagenesis reveals CD66 receptor residues required for neisserial Opa protein binding. J Exp Med 190:331–340
Chen T, Grunert F, Medina-Marino A, Gotschlich EC (1997) Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. J Exp Med 185:1557–1564
Clark MA, Hirst BH (2002) Expression of junction-associated proteins differentiates mouse intestinal M cells from enterocytes. Histochem Cell Biol 118:137–147
Clark MA, Hirst BH, Jepson MA (1998) M-cell surface β1 integrin expression and invasion-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells. Infect Immun 66:1237–1243
Drzeniek Z, Lamerz R, Fenger U, Wagener C, Haubeck HD (1991) Identification of membrane antigens in granulocytes and colonic carcinoma cells by a monoclonal antibody specific for biliary glycoprotein, a member of the carcinoembryonic antigen family. Cancer Lett 56:137–139
Dveksler GS, Dieffenbach CW, Cardellichio CB, McCuaig K, Pensiero MN, Jiang GS, Beauchemin N, Holmes KV (1993) Several members of the mouse carcinoembryonic antigen-related glycoprotein family are functional receptors for coronovirus mouse hepatitis virus-A59. J Virol 67:1–8
Fahlgren A, Baranov V, Frangsmyr L, Zoubir F, Hammarstrom M-L, Hammarstrom S (2003) Interferon-γ tempers the expression of carcinoembryonic antigen family molecules in human colon cells: a possible role in innate mucosal defense. Scand J Immunol 58:628–641
Frangsmyr L, Baranov V, Prall F, Yeung MM-W, Wagener C, Hammarstrom S (1995) Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa. Cancer Res 55:2963–2967
Frangsmyr L, Baranov V, Hammarstrom S (1999) Four carcinoembryonic antigen subfamily members, CEA, NCA, BGP and CGM2, selectively expressed in the normal human colonic epithelium, are integral components of the fuzzy coat. Tumor Biol 20:277–292
Gebert A, Fassbender S, Werner K, Weissferdt A (1999) The development of M cells in Peyer’s patches is restricted to specialized dome-associated crypts. Am J Pathol 154:1573–1582
Giannasca PJ, Giannasca KT, Falk P, Gordon JI, Neutra MR (1994) Regional differences in glycoconjugates of intestinal M cells in mice: potential targets for mucosal vaccines. Am J Physiol 267:G1108–G1121
Gray-Owen SD, Dehio C, Haude A, Grunert F, Meyer TF (1997) CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes. EMBO J 16:3435–3445
Guignot J, Peiffer I, Bernet-Camard MF, Lublin DM, Carnoy C, Moseley SL, Servin AL (2000) Recruitment of CD55 and CD66e brush border-associated glycosyl-phosphatidylinositol-anchored proteins by members of the Afa/Dr diffusely adhering family of Escherichia coli that infect the human polarized intestinal Caco-2/TC7 cells. Infect Immun 68:3554–3563
Hammarstrom S (1999) The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9:67–81
Hammarstrom S, Baranov V (2001) Is there a role for CEA in innate immunity in the colon? Trends Microbiol 9:119–125
Hammarstrom S, Olsen A, Teglund S, Baranov V (1998) The nature and expression of the human CEA family. In: Stanners CP (ed) Cell adhesion and communication mediated by the CEA family: basic and clinical perspectives, Harwood Academic, Amsterdam, pp 1–30
Hill DJ, Virji M (2003) A novel cell-binding mechanism of Moraxella catarrhalis ubiquitous surface protein UspA: specific targeting of the N-domain of carcinoembryonic antigen-related cell adhesion molecules by UspA1. Mol Microbiol 48:117–129
Hill DJ, Toleman MA, Evans DJ, Villullas S, Van Alphen L, Virji M (2001) The variable P5 proteins of typeable and non-typeable Haemophilus influenzae target human CEACAM1. Mol Microbiol 39:850–862
Jepson MA, Clark MA (1998) Studying M cells and their role in infection. Trends Microbiol 6:359–365
Jepson MA, Clark MA, Foster N, Mason CM, Bennett MK, Simmons NL, Hirst BH (1996) Targeting to intestinal M cells. J Anat 189:507–516
Karlsson KA (1998) Meaning and therapeutic potential of microbial recognition of host glycoconjugates. Mol Microbiol 29:1–11
Kerneis S, Bogdanova A, Colucci-Guyon E, Kraehenbuhl JP, Pringault E (1996) Cytosolic distribution of villin in M cells from mouse Peyer’s patches correlates with the absence of a brush border. Gastroenterology 110:515–521
Kraehenbuhl JP, Neutra MR (2000) Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 16:301–332
Leusch HG, Hefta SA, Drzeniek Z, Hummel K, Markos-Pusztai Z, Wagener C (1990) Escherichia coli of human origin binds to carcinoembryonic antigen (CEA) and non-specific crossreacting antigen (NCA). FEBS Lett 261:405–409
Leusch HG, Drzeniek Z, Markos-Pusztai Z, Wagener C (1991) Binding of Escherichia coli and Salmonella strains to members of the carcinoembryonic antigen family: differential binding inhibition by aromatic α-glycosides of mannose. Infect Immun 59:2051–2057
Nap M, Hammarstrom ML, Bormer O, Hammarstrom S, Wagener C, Handt S, Schreyer M, Mach JP, Buchegger F, von Kleist S, et al (1992) Specificity and affinity of monoclonal antibodies against carcinoembryonic antigen. Cancer Res 52:2329–2339
Nedellec P, Dveksler GS, Daniels E, Turbide C, Chow B, Basile AA, Holmes KV, Beauchemin N (1994) Bgp2, a new member of the carcinoembryonic antigen-related gene family, encodes an alternative receptor for mouse hepatitis viruses. J Virol 68:4525–4537
Obrink B (1997) CEA adhesion molecules: multifunctional proteins with signal-regulatory properties. Curr Opin Cell Biol 9:616–626
Owen RL (1999) Uptake and transport of intestinal macromolecules and microorganisms by M cells in Peyer’s patches: a personal and historical perspective. Semin Immunol 11:157–163
Popp A, Dehio C, Grunert F, Meyer TF, Gray-Owen SD (1999) Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding. Cell Microbiol 1:169–181
Prall F, Nollau P, Neumaier M, Haubeck HD, Drzeniek Z, Helmchen U, Loning T, Wagener C (1996) CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues. J Histochem Cytochem 44:35–41
Sansonetti PJ, Phalipon A (1999) M cells as ports of entry for enteroinvasive pathogens: mechanisms of interaction, consequences for the disease process. Semin Immunol 11:193–203
Sauter SL, Rutherfurd SM, Wagener C, Shively JE, Hefta SA (1991) Binding of nonspecific cross-reacting antigen, a granulocyte membrane glycoprotein, to Escherichia coli expressing type 1 fimbriae. Infect Immun 59:2485–2493
Siebers A, Finlay BB (1996) M cells and the pathogenesis of mucosal and systemic infections. Trends Microbiol 4:22–29
Toleman M, Aho E, Virji M (2001) Expression of pathogen-like Opa adhesins in commensal Neisseria: genetic and functional analysis. Cell Microbiol 3:33–44
Virji M, Watt SM, Barker S, Makepeace K, Doyonnas R (1996) The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitidis and Neisseria gonorrhoeae. Mol Microbiol 22:929–939
Virji M, Evans D, Hadfield A, Grunert F, Teixeira AM, Watt SM (1999) Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules. Mol Microbiol 34:538–551
Virji M, Evans D, Griffith J, Hill D, Serino L, Hadfield A, Watt SM (2000) Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae. Mol Microbiol 36:784–795
Acknowledgements
This work was supported by grants from the Swedish Cancer Society and the Swedish Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baranov, V., Hammarström, S. Carcinoembryonic antigen (CEA) and CEA-related cell adhesion molecule 1 (CEACAM1), apically expressed on human colonic M cells, are potential receptors for microbial adhesion. Histochem Cell Biol 121, 83–89 (2004). https://doi.org/10.1007/s00418-003-0613-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00418-003-0613-5