Abstract
Mucosal immune responses include a major B-cell component characterized by surface IgA-positive (SIgA+) B-cells that become plasma cells which produce polymeric IgA antibody (Ab). In addition, both T-helper (Th) cells and cytotoxic T-lymphocytes (CTLs) are induced in mucosa-associated lymphoreticular tissues (MALT) (1). These B- and T-cell responses can be induced by pathogens in organized mucosal inductive sites. In fact, the host has evolved a sophisticated network of cells and molecules that maintain the homeostasis of exposed mucosal surfaces (1,2). This system, termed MALT, is anatomically and functionally distinct from the systemic counterpart and is strategically located at the portal of entry of most microorganisms, including specific pathogens. Prior to the development of acquired immune responses, the mucosa are protected by innate defenses including the physical barrier provided by epithelial cells, secreted molecules with antibacterial activity, and the cytolytic activity of natural killer (NK) cells. However, effective protection against virulent mucosal pathogens requires prophylactic immune responses that can be achieved by mucosal vaccines, which, in contrast to systemic vaccines, can trigger both mucosal and systemic immunity. A major challenge for the development of mucosal vaccines will be to overcome the natural tendency of the host to suppress immune responses to orally administered antigens, a state commonly termed oral tolerance. In addition, effective protection against infectious agents will require the development of safe mucosal vaccines capable of promoting targeted immune responses.
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References
McGhee JR, Lamm ME, Strober W. Mucosal immune responses: an overview. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 485–506.
McGhee JR, Kiyono H. The mucosal immune system. In: Paul WE (ed). Fundamental Immunology. Philadelphia: Lippincott-Raven, 1999, pp. 909–945.
Bienenstock J, McDermot MR, Clancy RL. Respiratory tract defenses: role of mucosal lymphoid tissues. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 283–292.
Pabst R. Is BALT a major component of the human lung immune system? Immunol Today 1992; 13: 119–122.
Owen RL, Jones AL. Epithelial cell specialization within human Peyer’s patches: an ultra-structural study of intestinal lymphoid follicles. Gastroenterology 1974; 66: 189–203.
Neutra MR, Frey A, Kraehenbuhl JP. Epithelial M cells: gateways for mucosal infection and immunization. Cell 1996; 86: 345–348.
Owen RL, Apple RT, Bhalla DK. Morphometric and cytochemical analysis of lysosomes in rat Peyer’s patch follicle epithelium: their reduction in volume fraction and acid phosphatase content in M cells compared to adjacent enterocytes. Anat Rec 1986; 216: 521–527.
Neutra MR, Kreahenbuhl JP. Cellular and molecular basis for antigen transport across epithelial barriers. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 110–114.
Wolf JL, Bye WA. The membranous epithelial (M) cell and the mucosal immune system. Ann Rev Medi 1984; 35: 95–112.
Gebert A, Rothkotter HJ, Pabst R. M cells in Peyer’s patches of the intestine. Int Rev Cytol 1996; 167: 91–159.
Ermak TH, Dougherty EP, Bhagat HR, Kabok Z, Pappo J. Uptake and transport of copolymer biodegradable microspheres by rabbit Peyer’s patch M cells. Cell Tissue Res 1995; 279: 433–436.
Kerneis S, Bogdanova A, Kraehenbuhl JP, Pringault E. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 1997; 277: 949–952.
Brandtzaeg P, Baklien K, Bjerke K, Rognum TO, Scott H, Valnes K. Nature and properties of the human gastrointestinal immune system. In: Miller K, Nicklin S (eds) Immunology of the Gastrointestinal Tract. Boca Raton, FL: CRC, 1987, pp. 1–85.
George A, Cebra JJ. Responses of single germinal-center B cells in T-cell-dependent microculture. Proc Natl Acad Sci USA 1991; 88: 11–15.
Butcher EC, Rouse RV, Coffman RL, Nottenburg CN, Hardy RR, Weissman IL. Surface phenotype of Peyer’s patch germinal center cells: implications for the role of germinal centers in B cell differentiation. J Immunol 1982; 129: 2698–2707.
Lebman DA, Griffin PM, Cebra JJ. Relationship between expression of IgA by Peyer’s patch cells and functional IgA memory cells. J Exp Med 1987; 166: 1405–1418.
Weinstein PD, Cebra JJ. The preference for switching to IgA expression by Peyer’s patch germinal center B cells is likely due to the intrinsic influence of their microenvironment. J Immunol 1991; 147: 4126–4135.
Erickson SL, de Sauvage FJ, Kikly K, et al. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 1994; 372: 560–563.
Rennert PD, Browning JL, Mebius R, Mackay F, Hochman PS. Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. J Exp Med 1996; 184: 1999–2006.
Yamamoto M, Rennert P, McGhee JR, et al. Alternate mucosal immune system: organized Peyer’s patches are not required for IgA responses in the gastrointestinal tract. J Immunol 2000; 164: 5184 5191.
Fujihashi K, Dohi T, Rennert PD, et al. Peyer’s patches are required for oral tolerance to proteins. Proc Natl Acad Sci USA 2001; 98: 3310–3315.
Quiding-Jarbrink M, Granstrom G, Nordstrom I, Holmgren J, Czerkinsky C. Induction of compartmentalized B-cell responses in human tonsils. Infect Immun 1995; 63: 853–857.
Lubeck MD, Natuk RJ, Chengalvala M, et al. Immunogenicity of recombinant adenovirushuman immunodeficiency virus vaccines in chimpanzees following intranasal administration. AIDS Res Hum Retroviruses 1994; 10: 1443–1449.
Gallichan WS, Rosenthal KL. Specific secretory immune responses in the female genital tract following intranasal immunization with a recombinant adenovirus expressing glycoprotein B of herpes simplex virus. Vaccine 1995; 13: 1589–1595.
Pal S, Peterson EM, de la Maza LM. Intranasal immunization induces long-term protection in mice against a Chlamydia trachomatis genital challenge. Infect Immun 1996; 64: 5341–5348.
Di Tommaso A, Saletti G, Pizza M, et al. Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant. Infect Immun 1996; 64: 974–979.
Staats HF, Jackson RJ, Marinaro M, Takahashi I, Kiyono H, McGhee JR. Mucosal immunity to infection with implications for vaccine development. Curr Opin Immunol 1994; 6: 572–583.
Russell MW, Moldoveanu Z, White PL, Sibert GJ, Mestecky J, Michalek SM. Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the cholera toxin B subunit. Infect Immun 1996; 64: 1272–1283.
Johansson EL, Rask C, Fredriksson M, Eriksson K, Czerkinsky C, Holmgren J. Antibodies and antibody-secreting cells in the female genital tract after vaginal or intranasal immunization with cholera toxin B subunit or conjugates. Infect Immun 1998; 66: 514–520.
Bergquist C, Johansson EL, Lagergard T, Holmgren J, Rudin A. Intranasal vaccination of humans with recombinant cholera toxin B subunit induces systemic and local antibody responses in the upper respiratory tract and the vagina. Infect Immun 1997; 65: 2676–2684.
Lehner T, Bergmeier LA, Panagiotidi C, et al. Induction of mucosal and systemic immunity to a recombinant simian immunodeficiency viral protein. Science 1992; 258: 1365–1369.
Lehner T, Brookes R, Panagiotidi C, et al. T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route. Proc Natl Acad Sci USA 1993; 90: 8638–8642.
Moldoveanu Z, Russell MW, Wu HY, Huang WQ, Compans RW, Mestecky J. Compartmentalization within the common mucosal immune system. Adv Exp Med Biol 1995; 371A: 97–101.
Craig SW, Cebra JJ. Peyer’s patches: an enriched source of precursors for IgA-producing immunocytes in the rabbit. J Exp Med 1971; 134: 188–200.
Craig SW, Cebra JJ. Rabbit Peyer’s patches, appendix, and popliteal lymph node B lymphocytes: a comparative analysis of their membrane immunoglobulin components and plasma cell precursor potential. J Immunol 1975; 114: 492–502.
McDermott MR, Bienenstock J. Evidence for a common mucosal immunologic system. I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J Immunol 1979; 122: 1892–1898.
McWilliams M, Phillips-Quagliata JM, Lamm ME. Characteristics of mesenteric lymph node cells homing to gut-associated lymphoid tissue in syngeneic mice. J Immunol 1975; 115: 54–58.
McWilliams M, Phillips-Quagliata JM, Lamm ME. Mesenteric lymph node B lymphoblasts which home to the small intestine are precommitted to IgA synthesis. J Exp Med 1977; 145: 866–875.
Roux ME, McWilliams M, Phillips-Quagliata JM, Weisz-Carrington P, Lamm ME. Origin of IgA-secreting plasma cells in the mammary gland. J Exp Med 1977; 146: 1311–1322.
Czerkinsky C, Prince SJ, Michalek SM, et al. IgA antibody-producing cells in peripheral blood after antigen ingestion: evidence for a common mucosal immune system in humans. Proc Natl Acad Sci USA 1987; 84: 2449–2453.
Kantele A, Arvilommi H, Jokinen I. Specific immunoglobulin-secreting human blood cells after peroral vaccination against Salmonella typhi. J Infect Dis 1986; 153: 1126–1131.
Quiding M, Nordstrom I, Kilander A, et al. Intestinal immune responses in humans. Oral cholera vaccination induces strong intestinal antibody responses and interferon-gamma production and evokes local immunological memory. J Clin Invest 1991; 88: 143–148.
Kraal G, Mebius RE. High endothelial venules: lymphocyte traffic control and controlled traffic. Adv Immunol 1997; 65: 347–395.
Butcher EC. Lymphocyte homing and intestinal immunity. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 507–522.
Berlin C, Berg EL, Briskin MJ, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74: 185–195.
Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 1993; 11: 767–804.
Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell 1990; 62: 3–6.
Holzmann B, McIntyre BW, Weissman IL. Identification of a murine Peyer’s patch-specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Cell 1989; 56: 37–46.
Bell RG, Issekutz T. Expression of a protective intestinal immune response can be inhibited at three distinct sites by treatment with anti-alpha 4 integrin. J Immunol 1993; 151: 4790–4802.
Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 1994; 152: 3282–3293.
Rott LS, Briskin MJ, Andrew DP, Berg EL, Butcher EC. A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation. J Immunol 1996; 156: 3727–3736.
Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA, Butcher EC. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 1998; 279: 381–384.
Gunn MD, Kyuwa S, Tam C, et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization [see comments]. J Exp Med 1999; 189: 451–460.
Zabel BA, Agace W, Campbell JJ, et al. Human G protein-coupled receptor GPR-9–6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokinemediated chemotaxis. J Exp Med 1999; 190: 1241–1256.
Csencsits KL, Jutila MA, Pascual DW. Nasal-associated lymphoid tissue: phenotypic and functional evidence for the primary role of peripheral node addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site. J Immunol 1999; 163: 1382–1389.
Richards IM, Kolbasa KP, Hatfield CA, et al. Role of very late activation antigen-4 in the antigen-induced accumulation of eosinophils and lymphocytes in the lungs and airway lumen of sensitized brown Norway rats. Am J Respir Cell Mol Biol 1996; 15: 172–183.
Quiding-Jabrink M, Nordstrom I, Granstrom G, et al. Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, enteric, and nasal immunizations. A molecular basis for the compartmentalization of effector B cell responses. J Clin Invest 1997; 99: 1281–1286.
Quayle AJ, Porter EM, Nussbaum AA, et al. Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 1998; 152: 1247–1258.
Porter EM, Liu L, Oren A, Anton PA, Ganz T. Localization of human intestinal defensin 5 in Paneth cell granules. Infect Immun 1997; 65: 2389–2395.
Porter EM, van Dam E, Valore EV, Ganz T. Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect Immun 1997; 65: 2396–3401.
Zhao C, Wang I, Lehrer RI. Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett 1996; 396: 319–322.
Singh PK, Jia HP, Wiles K, et al. Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci USA 1998; 95: 14961–14966.
Mathews M, Jia HP, Guthmiller JM, et al. Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immun 1999; 67: 2740–2745.
O’Neil DA, Porter EM, Elewaut D, et al. Expression and regulation of the human betadefensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 1999; 163: 6718–6724.
Weinrauch Y, Elsbach P, Madsen LM, Foreman A, Weiss J. The potent anti-Staphylococcus aureus activity of a sterile rabbit inflammatory fluid is due to a 14-kD phospholipase A2. J Clin Invest 1996; 97: 250–257.
Harwig SS, Tan L, Qu XD, Cho Y, Eisenhauer PB, Lehrer RI. Bactericidal properties of murine intestinal phospholipase A2. J Clin Invest 1995; 95: 603–610.
Moriuchi M, Moriuchi H. A milk protein lactoferrin enhances human T cell leukemia virus type i and suppresses HIV-1 infection. J Immunol 2001; 166: 4231–4236.
Jung HC, Eckmann L, Yang SK, et al. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 1995; 95: 55–65.
Mayer L, Blumberg RS. Antigen presentating cells: epithelial cells. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 365–379.
Laurent F, Eckmann L, Savidge TC, et al. Cryptosporidium parvum infection of human intestinal epithelial cells induces the polarized secretion of C-X-C chemokines. Infect Immun 1997; 65: 5067–5073.
Yang SK, Eckmann L, Panja A, Kagnoff MF. Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 1997; 113: 1214–1223.
Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF. Regulated MIP3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol (Gastrointest Liver Physiol) 2001; 280: G710 - G719.
Dwinell MB, Lugering N, Eckmann L, Kagnoff ME Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology 2001; 120: 49–59.
Boismenu R, Feng L, Xia YY, Chang JC, Havran WL. Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. J Immunol 1996; 157: 985–992.
Hedrick JA, Saylor V, Figueroa D, et al. Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo. J Immunol 1997; 158: 1533–1540.
Tagliabue A, Befus AD, Clark DA, Bienenstock J. Characteristics of natural killer cells in the murine intestinal epithelium and lamina propria. J Exp Med 1982; 155: 1785–1796.
Roberts AI, O’Connell SM, Biancone L, Brolin RE, Ebert EC. Spontaneous cytotoxicity of intestinal intraepithelial lymphocytes: clues to the mechanism. Clin Exp Immunol 1993; 94: 527–532.
Lillehoj HS. Intestinal intraepithelial and splenic natural killer cell responses to Eimerian infections in inbred chickens. Infect Immun 1989; 57: 1879–1884.
Carman PS, Ernst PB, Rosenthal KL, Clark DA, Befus AD, Bienenstock J. Intraepithelial leukocytes contain a unique subpopulation of NK-like cytotoxic cells active in the defense of gut epithelium to enteric murine coronavirus. J Immunol 1986; 136: 1548–1553.
Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 1989; 320: 1731–1735.
Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989; 7: 145–173.
Kobayashi M, Fitz L, Ryan M, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989; 170: 827–845.
Chan SH, Perussia B, Gupta JW, et al. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 1991; 173: 869–879.
Snapper CM, Paul WE. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 1987; 236: 944–947.
Finkelman FD, Holmes J, Katona IM, et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol 1990; 8: 303–333.
Esser C, Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol 1990; 8: 717–735.
Coffman RL, Seymour BW, Lebman DA, et al. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol Rev 1998; 102: 5–28.
Gajewski TF, Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Thl murine helper T lymphocyte clones. J Immunol 1988; 140: 4245–4252.
Golding B. Cytokine regulation of humoral immune responses. Topics Vaccine Adjuvant Res 1991, pp. 37–45.
Bonecchi R, Bianchi G, Bordignon PP, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (This) and Th2s. J Exp Med 1998; 187: 129–134.
Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187: 875–883.
Imai T, Nagira M, Takagi S, et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol 1999; 11: 81–88.
Beagley KW, Eldridge JH, Kiyono H, et al. Recombinant murine IL-5 induces high rate IgA synthesis in cycling IgA-positive Peyer’s patch B cells. J Immunol 1988; 141: 2035–2042.
Beagley KW, Eldridge JH, Lee F, et al. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J Exp Med 1989; 169: 2133–2148.
Beagley KW, Eldridge JH, Aicher WK, et al. Peyer’s patch B cells with memory cell characteristics undergo terminal differentiation within 24 hours in response to interleukin-6. Cytokine 1991; 3: 107–116.
Fujihashi K, McGhee JR, Lue C, et al. Human appendix B cells naturally express receptors for and respond to interleukin 6 with selective IgAl and IgA2 synthesis. J Clin Invest 1991; 88: 248–252.
Ramsay AJ, Husband AJ, Ramshaw IA, et al. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science 1994; 264: 561–563.
Bromander AK, Ekman L, Kopf M, Nedrud JG, Lycke NY. IL-6-deficient mice exhibit normal mucosal IgA responses to local immunizations and Helicobacter felis infection. J Immunol 1996; 156: 4290–4207.
Briere F, Bridon JM, Chevet D, et al. Interleukin 10 induces B lymphocytes from IgAdeficient patients to secrete IgA. J Clin Invest 1994; 94: 97–104.
Defrance T, Vanbervliet B, Briere F, Durand I, Rousset F, Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med 1992; 175: 671–682.
Nonoyama S, Farrington M, Ishida H, Howard M, Ochs HD. Activated B cells from patients with common variable immunodeficiency proliferate and synthesize immunoglobulin. J Clin Invest 1993; 92: 1282–1287.
Mega J, McGhee JR, Kiyono H. Cytokine-and Ig-producing T cells in mucosal effector tissues: analysis of IL-5- and IFN-gamma-producing T cells, T cell receptor expression, and IgA plasma cells from mouse salivary gland-associated tissues. J Immunol 1992; 148: 2030–2039.
Taguchi T, McGhee JR, Coffman RL, et al. Analysis of Thl and Th2 cells in murine gut-associated tissues. Frequencies of CD4+ and CD8+ T cells that secrete IFN-gamma and IL-5. J Immunol 1990; 145: 68–77.
Kauppi-Korkeila M, van Alphen L, Madore D, Saarinen L, Kayhty H. Mechanism of antibody-mediated reduction of nasopharyngeal colonization by Haemophilus influenzae type b studied in an infant rat model. J Infect Dis 1996; 174: 1337–1340.
Davin JC, Senterre J, Mahieu PR. The high lectin-binding capacity of human secretory IgA protects nonspecifically mucosae against environmental antigens. Biol Neonate 1991; 59: 121–125.
Wold AE, Mestecky J, Tomana M, et al. Secretory immunoglobulin A carries oligosaccharide receptors for Escherichia coli type 1 fimbrial. Infect Immun 1990; 58: 3073–3077.
Wold AE, Motas C, Svanborg C, Mestecky J. Lectin receptors on IgA isotypes. Scand J Immunol 1994; 39: 195–201.
Armstrong SJ, Dimmock NJ. Neutralization of influenza virus by low concentrations of hemagglutinin-specific polymeric immunoglobulin A inhibits viral fusion activity, but activation of the ribonucleoprotein is also inhibited. J Virol 1992; 66: 3823–3832.
Mazanec MB, Coudret CL, Fletcher DR. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J Virol 1995; 69: 1339–1343.
Mazanec MB, Kaetzel CS, Lamm ME, Fletcher D, Nedrud JG. Intracellular neutralization of virus by immunoglobulin A antibodies. Pro Natl Acad Sci USA 1992; 89: 6901–6905.
Burns JW, Siadat-Pajouh M, Krishnaney AA, Greenberg HB. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 1996; 272: 104–107.
Bomsel M, Heyman M, Hocini H, et al. Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dIgA or IgM. Immunity 1998; 9: 277–287.
Griffiss JM, Goroff DK. IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms. J Immunol 1983; 130: 2882–2885.
Russell MW, Mansa B. Complement-fixing properties of human IgA antibodies. Alternative pathway complement activation by plastic-bound, but not specific antigen-bound, IgA. Scand J Immunol 1989; 30: 175–183.
Wolf HM, Fischer MB, Puhringer H, Samstag A, Vogel E, Eibl MM. Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) in human monocytes. Blood 1994; 83: 1278–1288.
Wolf HM, Hauber I, Gulle H, et al. Anti-inflammatory properties of human serum IgA: induction of IL-1 receptor antagonist and Fc alpha R (CD89)-mediated down-regulation of tumour necrosis factor-alpha (TNF-alpha) and IL-6 in human monocytes. Clin Exp Immunol 1996; 105: 537–543.
Offit PA, Cunningham SL, Dudzik KI. Memory and distribution of virus-specific cytotoxic T lymphocytes (CTLs) and CTL precursors after rotavirus infection. J Virol 1991; 65: 1318–1324.
London SD, Rubin DH, Cebra JJ. Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer’s patches. J Exp Med 1987; 165: 830–847.
London SD, Cebra-Thomas JA, Rubin DH, Cebra JJ. CD8 lymphocyte subpopulations in Peyer’s patches induced by reovirus serotype 1 infection. J Immunol 1990; 144: 3187–3194.
Issekutz TB. The response of gut-associated T lymphocytes to intestinal viral immunization. J Immunol 1984; 133: 2955–2960.
Marx PA, Compans RW, Gettie A, et al. Protection against vaginal SIV transmission with microencapsulated vaccine. Science 1993; 260: 1323–1327.
Miller CJ, Alexander NJ, Sutjipto S, et al. Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus. J Virol 1989; 63: 4277–4284.
Lohman BL, Miller CJ, McChesney MB. Antiviral cytotoxic T lymphocytes in vaginal mucosa of simian immunodeficiency virus-infected rhesus macaques. J Immunol 1995; 155: 5855–5860.
Miller CJ, McChesney MB, Lu X, et al. Rhesus macaques previously infected with simian/human immunodeficiency virus are protected from vaginal challenge with pathogenic SIVmac239. J Virol 1997; 71: 1911–1921.
Miller CJ. Mucosal transmission of simian immunodeficiency virus. Curr Top Microbiol Immunol 1994; 188: 107–122.
Porgador A, Staats HF, Faiola B, Gilboa E, Palker TJ. Intranasal immunization with CTL epitope peptides from HIV-1 or ovalbumin and the mucosal adjuvant cholera toxin induces peptide-specific CTLs and protection against tumor development in vivo. J Immunol 1997; 158: 834–841.
Elson CO, Ealding W. Generalized systemic and mucosal immunity in mice after mucosal stimulation with cholera toxin. J Immunol 1984; 132: 2736–2741.
Elson CO, Ealding W. Cholera toxin feeding did not induce oral tolerance in mice and abrogated oral tolerance to an unrelated protein antigen. J Immunol 1984; 133: 2892–2897.
Clements JD, Hartzog NM, Lyon FL. Adjuvant activity of Escherichia coli heat-labile enterotoxin and effect on the induction of oral tolerance in mice to unrelated protein antigens. Vaccine 1988; 6: 269–277.
Lycke N, Holmgren J. Strong adjuvant properties of cholera toxin on gut mucosal immune responses to orally presented antigens. Immunology 1986; 59: 301–308.
VanCott JL, Staats HF, Pascual DW, et al. Regulation of mucosal and systemic antibody responses by T helper cell subsets, macrophages, and derived cytokines following oral immunization with live recombinant Salmonella. J Immunol 1996; 156: 1504–1514.
Van Ginkel FW, Liu C, Simecka JW, et al. Intratracheal gene delivery with adenoviral vector induces elevated systemic IgG and mucosal IgA antibodies to adenovirus and betagalactosidase. 1995; Hum Gene Ther 1995; 6: 895–903.
Gill DM. The arrangement of subunits in cholera toxin. Biochemistry 1976; 15: 1242–1248.
Spangler BD. Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol Rev 1992; 56: 622–647.
Heyningen SV. Cholera toxin: interaction of subunits with ganglioside GM1. Science 1974; 183: 656–657.
Field M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrheal disease (1). N Engl J Med 1989; 321: 800–806.
Dallas WS, Falkow S. Amino acid sequence homology between cholera toxin and Escherichia coli heat-labile toxin. Nature 1980; 288: 499–501.
Tsuji T, Inoue T, Miyama A, Okamoto K, Honda T, Miwatani T. A single amino acid substitution in the A subunit of Escherichia coli enterotoxin results in a loss of its toxic activity. J Biol Chem 1990; 265: 22520–22525.
Harford S, Dykes CW, Hobden AN, Read MJ, Halliday IJ. Inactivation of the Escherichia coli heat-labile enterotoxin by in vitro mutagenesis of the A-subunit gene. Eur J Biochem 1989; 183: 311–316.
Yamamoto S, Takeda Y, Yamamoto M, et al. Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity. J Exp Med 1997; 185: 1203–1210.
Yamamoto S, Kiyono H, Yamamoto M, et al. A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Pro Natl Acad Sci USA 1997; 94: 5267–5272.
Yamamoto M, Kiyono H, Yamamoto S, et al. Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant. J Immunol 1999; 162: 7015–7021.
Cong Y, Weaver CT, Elson CO. The mucosal adjuvanticity of cholera toxin involves enhancement of costimulatory activity by selective upregulation of B7.2 expression. J Immunol 1997; 159: 5301–5308.
Douce G, Fontana M, Pizza M, Rappuoli R, Dougan G. Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin. Infect Immun 1997; 65: 2821–2828.
Douce G, Turcotte C, Cropley I, et al. Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants. Proc Natl Acad Sci USA 1995; 92: 1644–1648.
Giuliani MM, Del Giudice G, Giannelli V, et al. Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity. J Exp Med 1998; 187: 1123–1132.
Rappuoli R, Pizza M, Douce G, Dougan G. Structure and mucosal adjuvanticity of cholera and Escherichia coli heat-labile enterotoxins. Immunol Today 1999; 20: 493–500.
Takahashi I, Marinaro M, Kiyono H, et al. Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J Infect Dis 1996; 173, no. 3: 627–635.
Agren LC, Ekman L, Lowenadler B, Lycke NY. Genetically engineered nontoxic vaccine adjuvant that combines B cell targeting with immunomodulation by cholera toxin Al subunit. J Immunol 1997; 158: 3936–3946.
Agren L, Sverremark E, Ekman L, et al. The ADP-ribosylating CTA1-DD adjuvant enhances T cell-dependent and independent responses by direct action on B cells involving anti-apoptotic Bc1–2- and germinal center-promoting effects. J Immunol 2000; 164: 6276–6286.
Agren LC, Ekman L, Lowenadler B, Nedrud JG, Lycke NY. Adjuvanticity of the cholera toxin Al-based gene fusion protein, CTA1-DD, is critically dependent on the ADPribosyltransferase and Ig-binding activity. J Immunol 1999; 162: 2432–2440.
Hajishengallis G, Hollingshead SK, Koga T, Russell MW. Mucosal immunization with a bacterial protein antigen genetically coupled to cholera toxin A2B subunits. J Immunol 1995; 154: 4322–4332.
Sun JB, Mielcarek N, Lakew M, et al. Intranasal administration of a Schistosoma man-soni glutathione S-transferase-cholera toxoid conjugate vaccine evokes antiparasitic and antipathological immunity in mice. J Immunol 1999; 163: 1045–1052.
Sun JB, Rask C, Olsson T, Holmgren J, Czerkinsky C. Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit. Proc Natl Acad Sci USA 1996; 93: 7196–7201.
Bergerot I, Ploix C, Petersen J, et al. A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc Natl Acad Sci USA 1997; 94: 4610–4614.
Marinaro M, Boyaka PN, Jackson RJ, et al. Use of intranasal IL-12 to target predominantly Thl responses to nasal and Th2 responses to oral vaccines given with cholera toxin. J Immunol 1999; 162: 114–121.
Boyaka PN, Marinaro M, Jackson RJ, et al. IL-12 is an effective adjuvant for induction of mucosal immunity. J Immunol 1999; 162: 122–128.
Arulanandam BP, O’Toole M, Metzger DW. Intranasal interleukin-12 is a powerful adjuvant for protective mucosal immunity. J Infect Dis 1999; 180: 940–949.
Staats HF, Ennis, Jr. FA. IL-1 is an effective adjuvant for mucosal and systemic immune responses when coadministered with protein immunogens. J Immunol 1999; 162: 6141–6147.
Marinaro M, Boyaka PN, Finkelman FD, et al. Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses. J Exp Med 1997; 185: 415–427.
Lillard JW, Jr, Boyaka PN, Chertov O, Oppenheim JJ, McGhee JR. Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc Natl Acad Sci USA 1999; 96: 651–656.
Lillard JW, Jr, Boyaka PN, Hedrick JA, Zlotnik A, McGhee JR. Lymphotactin acts as an innate mucosal adjuvant. J Immunol 1999; 162: 1959–1965.
Lillard JW, Boyaka PN, Taub DD, McGhee JR. RANTES potentiates antigen-specific mucosal immune responses. J Immunol 2001; 166: 162–169.
Krieg AM. CpG DNA: a pathogenic factor in systemic lupus erythematosus? J Clin Immunol 1995; 15: 284–292.
Tighe H, Corr M, Roman M, Raz E. Gene vaccination: plasmid DNA is more than just a blueprint. Immunol Today 1998; 19: 89–97.
Roman M, Martin-Orozco E, Goodman JS, et al. Immunostimulatory DNA sequences function as T helper- 1-promoting adjuvants. Nat Med 1997; 3: 849–854.
Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci USA 1996; 93: 2879–2883.
Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Thl) immunity. J Exp Med 1997; 186: 1623–1631.
Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM. CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 1998; 16: 1216–1224.
McCluskie MJ, Davis HL. CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J Immunol 1998; 161: 4463–4466.
Elson CO, Dertzbaugh MT. Mucosal adjuvants. In: Ogra PL, et al. (eds). Mucosal Immunology. San Diego: Academic, 1999, pp. 817–838.
Mowat AM, Donachie AM, Reid G, Jarrett O. Immune-stimulating complexes containing Quil A and protein antigen prime class I MHC-restricted T lymphocytes in vivo and are immunogenic by the oral route. Immunology 1991; 72: 317–322.
Kensil CR, Kammer R. QS-21: A water-soluble triterpene glycoside adjuvant. Expert Opin Invest Drugs 1998; 7: 1475–1482.
Kensil CR, Patel U, Lennick M, and Marciani D. Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J Immunol 1991; 146: 431–437.
Livingston P, Zhang S, Adluri S, et al. Tumor cell reactivity mediated by IgM antibodies in sera from melanoma patients vaccinated with GM2 ganglioside covalently linked to KLH is increased by IgG antibodies. Cancer Immunol Immunother 1997; 43: 324–330.
Coughlin RT, Fattom A, Chu C, White AC, Winston S. Adjuvant activity of QS-21 for experimental E. coli 018 polysaccharide vaccines. Vaccine 1995. 13: 17–21.
Newman MJ, Wu JY, Gardner BH, et al. Saponin adjuvant induction of ovalbuminspecific CD8+ cytotoxic T lymphocyte responses. J Immunol 1992; 148: 2357–2362.
Sasaki S, Sumino K, Hamajima K, et al. Induction of systemic and mucosal immune responses to human immunodeficiency virus type 1 by a DNA vaccine formulated with QS-21 saponin adjuvant via intramuscular and intranasal routes. J Virol 1998; 72: 4931–4939.
Boyaka PN, Marinaro M, Jackson RJ, et al. Oral QS-21 requires early IL-4 help for induction of mucosal and systemic immunity. J Immunol 2001; 166: 2283–2290.
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Boyaka, P.N., McGhee, J.R. (2002). Immune Defense at Mucosal Surfaces. In: Jacobson, J.M. (eds) Immunotherapy for Infectious Diseases. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-171-8_3
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DOI: https://doi.org/10.1007/978-1-59259-171-8_3
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