Mucosa-Associated Lymphoid Tissue and Dynamics of Lymphoid Cells in the Five Different Compartments in Allergic Diseases

  • Satoshi Fukuyama
  • Takahiro Nagatake
  • Hiroshi Kiyono
Part of the Allergy Frontiers book series (ALLERGY, volume 2)


Mucosal surfaces, including those of the respiratory and gastrointestinal tracts, are continuously exposed to numerous kinds of environmental antigens and allergens and to the risk of invasion by pathogens. The mucosal immune system thus provides the first line of defense against mucosally encountered pathogens and allergens. It also serves an important role in the development of cohabitation by commensal flora and nutrient antigens, thereby facilitating the development of an appropriate immunological response and physiological homeostasis between the host and its outside environment. For the execution of these dynamic immune responses in the aerodigestive tract, mucosa-associated lymphoid tissue (MALT), which consists of nasopharynx-associated lymphoid tissue (NALT), bronchus-associated lymphoid tissue (BALT), and gut-associated lymphoid tissue (GALT), has been shown to be an important site for the induction of antigen-specific immune responses in both the mucosal and systemic compartments of immunity. Mucosal tolerance initiated in these inductive tissues is also necessary for the prevention or control of harmful immune responses against inhaled airborne antigens and ingested food antigens. Disruption of the induction of mucosal tolerance is one of the factors that contribute to the development of allergic disease. Thus, the elucidation and understanding of the molecular and cellular uniqueness of the mucosal immune system is necessary for the prevention and control of hyperallergic responses and thus the maintenance of healthy functioning. The emphasis of this chapter is on the introduction of dynamism in MALT organogenesis as well as the functional role of these inductive tissues within the mucosal immune system.


Treg Cell Oral Tolerance Mucosal Immune System Mucosal Tolerance Nasal Immunization 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Mestecky J, Blumberg R, Kiyono H, McGhee JR (2003) The mucosal immune system. In: Paul WE (ed) Fundamental Immunology, 5th edn. Academic Press, San Diego, CA, pp 965–1020Google Scholar
  2. 2.
    Nochi T, Kiyono H (2006) Innate immunity in the mucosal immune system. Curr. Pharm. 12:4203–4213CrossRefGoogle Scholar
  3. 3.
    Mowat AM (2003) Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3:331–341PubMedCrossRefGoogle Scholar
  4. 4.
    Kunisawa J, Fukuyama S, Kiyono H (2005) Mucosa-associated lymphoid tissues in the aero-digestive tract: their shared and divergent traits and their importance to the orchestration of the mucosal immune system. Curr. Mol. Med. 5:557–572PubMedCrossRefGoogle Scholar
  5. 5.
    Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, Kucharzik T, Shirakawa AK, Marquez G, Farber JM, Williams I, Iwasaki A (2003) CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer's patch CD11b+ dendritic cells. J. Immunol. 171:2797–2803PubMedGoogle Scholar
  6. 6.
    Neutra MR, Frey A, Kraehenbuhl JP (1996) Epithelial M cells: gateways for mucosal infection and immunization. Cell 86:345–348PubMedCrossRefGoogle Scholar
  7. 7.
    Neutra MR, Mantis NJ, Kraehenbuhl JP (2001) Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2:1004–1009PubMedCrossRefGoogle Scholar
  8. 8.
    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. 11:157–163PubMedCrossRefGoogle Scholar
  9. 9.
    Iwasaki A, Kelsall BL (2000) Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191:1381–1394PubMedCrossRefGoogle Scholar
  10. 10.
    Salazar-Gonzalez RM, Niess JH, Zammit DJ, Ravindran R, Srinivasan A, Maxwell JR, Stoklasek T, Yadav R, Williams IR, Gu X, McCormick BA, Pazos MA, Vella AT, Lefrancois L, Reinecker HC, McSorley SJ (2006) CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity 24:623–632PubMedCrossRefGoogle Scholar
  11. 11.
    Fleeton MN, Contractor N, Leon F, Wetzel JD, Dermody TS, Kelsall BL (2004) Peyer's patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice. J. Exp. Med. 200:235–245PubMedCrossRefGoogle Scholar
  12. 12.
    Iwasaki A, Kelsall BL (2001) Unique functions of CD11b+, CD8α+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166:4884–4890PubMedGoogle Scholar
  13. 13.
    Asselin-Paturel C, Brizard G, Pin JJ, Briére F, Trinchieri G (2003) Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J. Immunol. 171:6466–6477Google Scholar
  14. 14.
    Contractor N, Louten J, Kim L, Biron CA, Kelsall BL (2007) Cutting edge: Peyer's patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL-10, TGFβ, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype. J. Immunol. 179:2690–2694PubMedGoogle Scholar
  15. 15.
    Weinstein PD, Cebra JJ (1991) 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. 147:4126–4135PubMedGoogle Scholar
  16. 16.
    Gohda M, Kunisawa J, Miura F, Kagiyama Y, Kurashima Y, Higuchi M, Ishikawa I, Ogahara I, Kiyono H (2008) Sphingosine 1-phosphate regulates the egress of IgA plasmablasts from Peyer's patches for intestinal IgA responses. J. Immunol. 180:5335–5343PubMedGoogle Scholar
  17. 17.
    Warnock RA, Campbell JJ, Dorf ME, Matsuzawa A, McEvoy LM, Butcher EC (2000) The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules. J. Exp. Med. 191:77–88PubMedCrossRefGoogle Scholar
  18. 18.
    Ebisuno Y, Tanaka T, Kanemitsu N, Kanda H, Yamaguchi K, Kaisho T, Akira S, Miyasaka M (2003) Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chem-oattractant is expressed in the high endothelial venules of lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules. J. Immunol. 171:1642–1646PubMedGoogle Scholar
  19. 19.
    Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC (1994) Role of α4-integrins in lymphocyte homing to mucosal tissues in vivo. J. Immunol. 152: 3282–3293PubMedGoogle Scholar
  20. 20.
    Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H (2006) The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT. J. Immunol. 176:43–51PubMedGoogle Scholar
  21. 21.
    Hamada H, Hiroi T, Nishiyama Y, Takahashi H, Masunaga Y, Hachimura S, Kaminogawa S, Takahashi-Iwanaga H, Iwanaga T, Kiyono H, Yamamoto H, Ishikawa H (2002) Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168:57–64PubMedGoogle Scholar
  22. 22.
    Eberl G, Littman DR (2004) Thymic origin of intestinal ab T cells revealed by fate mapping of RORγt+ cells. Science 305:248–251PubMedCrossRefGoogle Scholar
  23. 23.
    Owen RL, Piazza AJ, Ermak TH (1991) Ultrastructural and cytoarchitectural features of lymphoreticular organs in the colon and rectum of adult BALB/c mice. Am. J. Anat. 190:10–18PubMedCrossRefGoogle Scholar
  24. 24.
    Dohi T, Fujihashi K, Rennert PD, Iwatani K, Kiyono H, McGhee JR (1999) Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses. J. Exp. Med. 189:1169–1180PubMedCrossRefGoogle Scholar
  25. 25.
    Lee AY, Chang SY, Kim JI, Cha HR, Jang MH, Yamamoto M, Kweon MN (2008) Dendritic cells in colonic patches and iliac lymph nodes are essential in mucosal IgA induction following intrarectal administration via CCR7 interaction. Eur. J. Immunol. 38:1127–1137PubMedCrossRefGoogle Scholar
  26. 26.
    Kweon MN, Yamamoto M, Rennert PD, Park EJ, Lee AY, Chang SY, Hiroi T, Nanno M, Kiyono H (2005) Prenatal blockage of lymphotoxin β receptor and TNF receptor p55 signaling cascade resulted in the acceleration of tissue genesis for isolated lymphoid follicles in the large intestine. J. Immunol. 174:4365–4372PubMedGoogle Scholar
  27. 27.
    Fu YX, Huang G, Matsumoto M, Molina H, Chaplin DD (1997) Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node. Proc. Natl. Acad. Sci. U.S.A. 94:5739–5743PubMedCrossRefGoogle Scholar
  28. 28.
    Hoshi H, Horie K, Tanaka K, Nagata H, Aizawa S, Hiramoto M, Ryouke T, Aijima H (2001) Patterns of age-dependent changes in the numbers of lymph follicles and germinal centres in somatic and mesenteric lymph nodes in growing C57Bl/6 mice. J. Anat. 198:189–205PubMedCrossRefGoogle Scholar
  29. 29.
    Csencsits KL, Jutila MA, Pascual DW (1999) Nasal-associated lymphoid tissue: pheno-typic 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. 163:1382–1389PubMedGoogle Scholar
  30. 30.
    Stenstad H, Ericsson A, Johansson-Lindbom B, Svensson M, Marsal J, Mack M, Picarella D, Soler D, Marquez G, Briskin M, Agace WW (2006) Gut-associated lymphoid tissue-primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine. Blood 107:3447–3454PubMedCrossRefGoogle Scholar
  31. 31.
    Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538PubMedCrossRefGoogle Scholar
  32. 32.
    Jang MH, Sougawa N, Tanaka T, Hirata T, Hiroi T, Tohya K, Guo Z, Umemoto E, Ebisuno Y, Yang BG, Seoh JY, Lipp M, Kiyono H, Miyasaka M (2006) CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176:803–810PubMedGoogle Scholar
  33. 33.
    Chang SY, Cha HR, Igarashi O, Rennert PD, Kissenpfennig A, Malissen B, Nanno M, Kiyono H, Kweon MN (2008) Cutting edge: langerin+ dendritic cells in the mesenteric lymph node set the stage for skin and gut immune system cross-talk. J. Immunol. 180:4361–4365PubMedGoogle Scholar
  34. 34.
    Kanamori Y, Ishimaru K, Nanno M, Maki K, Ikuta K, Nariuchi H, Ishikawa H (1996) Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184:1449–1459PubMedCrossRefGoogle Scholar
  35. 35.
    Saito H, Kanamori Y, Takemori T, Nariuchi H, Kubota E, Takahashi-Iwanaga H, Iwanaga T, Ishikawa H (1998) Generation of intestinal T cells from progenitors residing in gut crypto-patches. Science 280:275–278PubMedCrossRefGoogle Scholar
  36. 36.
    Lügering A, Kucharzik T, Soler D, Picarella D, Hudson JT 3rd, Williams IR (2003) Lymphoid precursors in intestinal cryptopatches express CCR6 and undergo dysregulated development in the absence of CCR6. J. Immunol. 171:2208–2215PubMedGoogle Scholar
  37. 37.
    Debertin AS, Tschernig T, Tonjes H, Kleemann WJ, Troger HD, Pabst R (2003) Nasal-associated lymphoid tissue (NALT): frequency and localization in young children. Clin. Exp. Immunol. 134:503–507PubMedCrossRefGoogle Scholar
  38. 38.
    Park HS, Francis KP, Yu J, Cleary PP (2003) Membranous cells in nasal-associated lymphoid tissue: a portal of entry for the respiratory mucosal pathogen group A streptococcus. J. Immunol. 171:2532–2537PubMedGoogle Scholar
  39. 39.
    Drayton DL, Bonizzi G, Ying X, Liao S, Karin M, Ruddle NH (2004) IκB kinase complex a kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue. J. Immunol. 173:6161–6168PubMedGoogle Scholar
  40. 40.
    Fukuyama S, Nagatake T, Kim DY, Takamura K, Park EJ, Kaisho T, Tanaka N, Kurono Y, Kiyono H (2006) Cutting edge: uniqueness of lymphoid chemokine requirement for the initiation and maturation of nasopharynx-associated lymphoid tissue organogenesis. J. Immunol. 177:4276–4280PubMedGoogle Scholar
  41. 41.
    Fukuyama S, Hiroi T, Yokota Y, Rennert PD, Yanagita M, Kinoshita N, Terawaki S, Shikina T, Yamamoto M, Kurono Y, Kiyono H (2002) Initiation of NALT organogenesis is independent of the IL-7R, LTβR, and NIK signaling pathways but requires the Id2 gene and CD3-CD4+CD45+ cells. Immunity 17:31–40PubMedCrossRefGoogle Scholar
  42. 42.
    Takamura K, Fukuyama S, Nagatake T, Kim DY, Kawamura A, Kawauchi H, Kiyono H (2007) Regulatory role of lymphoid chemokine CCL19 and CCL21 in the control of allergic rhinitis. J. Immunol. 179:5897–5906PubMedGoogle Scholar
  43. 43.
    Bienenstock J, Johnston N, Perey DYE (1973) Bronchial lymphoid tissue. I. Morphologic characteristics. Lab. Invest. 28:686PubMedGoogle Scholar
  44. 44.
    Bienenstock J, Johnston N, Perey DYE (1973) Bronchial lymphoid tissue. II. Functional characteristics. Lab. Invest. 28:693PubMedGoogle Scholar
  45. 45.
    Tango M, Suzuki E, Gejyo F, Ushiki T (2000) The presence of specialized epithelial cells on the bronchus-associated lymphoid tissue (BALT) in the mouse. Arch. Histol. Cytol. 63:81–89PubMedCrossRefGoogle Scholar
  46. 46.
    Bienenstock J, McDermott MR (2005) Bronchus- and nasal-associated lymphoid tissues. Immunol. Rev. 206:22–31PubMedCrossRefGoogle Scholar
  47. 47.
    Otsuki Y, Ito Y, Magari S (1989) Lymphocyte subpopulations in high endothelial venules and lymphatic capillaries of bronchus-associated lymphoid tissue (BALT) in the rat. Am. J. Anat. 184:139–146PubMedCrossRefGoogle Scholar
  48. 48.
    Xu B, Wagner N, Pham LN, Magno V, Shan Z, Butcher EC, Michie SA (2003) Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, α4(31 integrin/VCAM-1, and LFA-1 adhesion pathways. J. Exp. Med. 197:1255–1267PubMedCrossRefGoogle Scholar
  49. 49.
    Feng CG, Britton WJ, Palendira U, Groat NL, Briscoe H, Bean AG (2000) Up-regulation of VCAM-1 and differential expansion of β integrin-expressing T lymphocytes are associated with immunity to pulmonary Mycobacterium tuberculosis infection. J. Immunol. 164:4853–4860PubMedGoogle Scholar
  50. 50.
    Cavallotti C, Bruzzone P, Tonnarini G, Cavallotti D (2004) Distribution of catecholaminer-gic neurotransmitters and related receptors in human bronchus-associated lymphoid tissue. Respiration 71:635–640PubMedCrossRefGoogle Scholar
  51. 51.
    Proskocil BJ, Fryer AD (2005) Beta2-agonist and anticholinergic drugs in the treatment of lung disease. Proc. Am. Thorac. Soc. 2:305–310PubMedCrossRefGoogle Scholar
  52. 52.
    Adachi S, Yoshida H, Kataoka H, Nishikawa S (1997) Three distinctive steps in Peyer's patch formation of murine embryo. Int. Immunol. 9:507–514PubMedCrossRefGoogle Scholar
  53. 53.
    Veiga-Fernandes H, Coles MC, Foster KE, Patel A, Williams A, Natarajan D, Barlow A, Pachnis V, Kioussis D (2007) Tyrosine kinase receptor RET is a key regulator of Peyer's patch organogenesis. Nature (Lond) 446:547–551CrossRefGoogle Scholar
  54. 54.
    Barlow A, de Graaff E, Pachnis V (2003) Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron 40:905–916PubMedCrossRefGoogle Scholar
  55. 55.
    Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70PubMedCrossRefGoogle Scholar
  56. 56.
    Yoshida H, Honda K, Shinkura R, Adachi S, Nishikawa S, Maki K, Ikuta K, Nishikawa SI (1999) IL-7 receptor α+ CD3- cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11:643–655PubMedCrossRefGoogle Scholar
  57. 57.
    Nishikawa S, Honda K, Vieira P, Yoshida H (2003) Organogenesis of peripheral lymphoid organs. Immunol. Rev. 195:72–80PubMedCrossRefGoogle Scholar
  58. 58.
    Mebius RE (2003) Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3:292–303PubMedCrossRefGoogle Scholar
  59. 59.
    Kiyono H, Fukuyama S (2004) NALT- versus Peyer's-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4:699–710PubMedCrossRefGoogle Scholar
  60. 60.
    Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S, Nishikawa S, Gruss P (1999) Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature (Lond) 397:702–706CrossRefGoogle Scholar
  61. 61.
    Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR (2004) An essential function for the nuclear receptor RORy(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5:64–73PubMedCrossRefGoogle Scholar
  62. 62.
    Adachi S, Yoshida H, Honda K, Maki K, Saijo K, Ikuta K, Saito T, Nishikawa SI (1998) Essential role of IL-7 receptor a in the formation of Peyer's patch anlage. Int. Immunol. 10:1–6PubMedCrossRefGoogle Scholar
  63. 63.
    Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, et al. (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–238PubMedCrossRefGoogle Scholar
  64. 64.
    Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI (2001) Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis. J. Exp. Med. 193:621–630PubMedCrossRefGoogle Scholar
  65. 65.
    Ansel KM, Ngo VN, Hyman PL, Luther SA, Förster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature (Lond) 406:309–314PubMedCrossRefGoogle Scholar
  66. 66.
    Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M (1996) A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87:1037–1047PubMedCrossRefGoogle Scholar
  67. 67.
    Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E, Lipp M (1999) CCR7 coordinates the primary immune response by establishing functional microenviron-ments in secondary lymphoid organs. Cell 99:23–33PubMedCrossRefGoogle Scholar
  68. 68.
    Finke D, Acha-Orbea H, Mattis A, Lipp M, Kraehenbuhl J (2002) CD4+CD3- cells induce Peyer's patch development: role of α4β1 integrin activation by CXCR5. Immunity 17:363–373PubMedCrossRefGoogle Scholar
  69. 69.
    Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C, Li ZW, Karin M, Ware CF, Green DR (2002) The lymphotoxin |3 receptor induces different patterns of gene expression via two NF-kB pathways. Immunity 17:525–535PubMedCrossRefGoogle Scholar
  70. 70.
    Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344–362PubMedCrossRefGoogle Scholar
  71. 71.
    Muller JR, Siebenlist U (2003) Lymphotoxin β receptor induces sequential activation of distinct NF-κB factors via separate signaling pathways. J. Biol. Chem. 278:12006–12012PubMedCrossRefGoogle Scholar
  72. 72.
    Weih F, Caamano J (2003) Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol. Rev. 195:91–105PubMedCrossRefGoogle Scholar
  73. 73.
    Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV, Schreiber RD (2001) Defective lymphotoxin β receptor-induced NF-κB transcriptional activity in NIK-deficient mice. Science 291:2162–2165PubMedCrossRefGoogle Scholar
  74. 74.
    Yilmaz ZB, Weih DS, Sivakumar V, Weih F (2003) RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J. 22:121–130PubMedCrossRefGoogle Scholar
  75. 75.
    Piao JH, Yoshida H, Yeh WC, Doi T, Xue X, Yagita H, Okumura K, Nakano H (2007) TNF receptor-associated factor 2-dependent canonical pathway is crucial for the development of Peyer's patches. J. Immunol. 178:2272–2277PubMedGoogle Scholar
  76. 76.
    Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J. Immunol. 170:5475–5482PubMedGoogle Scholar
  77. 77.
    Fagarasan S, Muramatsu M, Suzuki K, Nagaoka H, Hiai H, Honjo T (2002) Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298:1424–1427PubMedCrossRefGoogle Scholar
  78. 78.
    Taylor RT, Lugering A, Newell KA, Williams IR (2004) Intestinal cryptopatch formation in mice requires lymphotoxin α and the lymphotoxin β receptor. J. Immunol. 173:7183–7189PubMedGoogle Scholar
  79. 79.
    Ivanov II, Diehl GE, Littman DR (2006) Lymphoid tissue inducer cells in intestinal immunity. Curr. Top. Microbiol. Immunol. 308:59–82PubMedCrossRefGoogle Scholar
  80. 80.
    Harmsen A, Kusser K, Hartson L, Tighe M, Sunshine MJ, Sedgwick JD, Choi Y, Littman DR, Randall TD (2002) Cutting edge: organogenesis of nasal-associated lymphoid tissue (NALT) occurs independently of lymphotoxin-α (LTα) and retinoic acid receptor-related orphan receptor-γ, but the organization of NALT is LTα dependent. J. Immunol. 168:986–990PubMedGoogle Scholar
  81. 81.
    Rangel-Moreno J, Moyron-Quiroz J, Kusser K, Hartson L, Nakano H, Randall TD (2005) Role of CXC chemokine ligand 13, CC chemokine ligand (CCL) 19, and CCL21 in the organization and function of nasal-associated lymphoid tissue. J. Immunol. 175:4904–4913PubMedGoogle Scholar
  82. 82.
    Ying X, Chan K, Shenoy P, Hill M, Ruddle NH (2005) Lymphotoxin plays a crucial role in the development and function of nasal-associated lymphoid tissue through regulation of chemokines and peripheral node addressin. Am. J. Pathol. 166:135–146PubMedGoogle Scholar
  83. 83.
    Drayton DL, Bonizzi G, Ying X, Liao S, Karin M, Ruddle NH (2004) IkB kinase complex a kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue. J. Immunol. 173:6161–6168PubMedGoogle Scholar
  84. 84.
    Tschernig T, Pabst R (2000) Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology 68:1–8PubMedCrossRefGoogle Scholar
  85. 85.
    Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10:927–934PubMedCrossRefGoogle Scholar
  86. 86.
    Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD (2006) Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116:3183–3194PubMedCrossRefGoogle Scholar
  87. 87.
    Kocks JR, Davalos-Misslitz AC, Hintzen G, Ohl L, Forster R (2007) Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J. Exp. Med. 204:723–734PubMedCrossRefGoogle Scholar
  88. 88.
    Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S (2000) Prostaglandin D2 as a mediator of allergic asthma. Science 287:2013–2017PubMedCrossRefGoogle Scholar
  89. 89.
    Hiramatsu K, Azuma A, Kudoh S, Desaki M, Takizawa H, Sugawara I (2003) Inhalation of diesel exhaust for three months affects major cytokine expression and induces bronchus-associated lymphoid tissue formation in murine lungs. Exp. Lung Res. 29:607–622PubMedCrossRefGoogle Scholar
  90. 90.
    Rangel-Moreno J, Moyron-Quiroz JE, Hartson L, Kusser K, Randall TD (2007) Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc. Natl. Acad. Sci. U.S.A. 104:10577–10582PubMedCrossRefGoogle Scholar
  91. 91.
    Conley ME, Delacroix DL (1987) Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann. Intern. Med. 106:892–899Google Scholar
  92. 92.
    Wijburg OL, Uren TK, Simpfendorfer K, Johansen FE, Brandtzaeg P, Strugnell RA (2006) Innate secretory antibodies protect against natural Salmonella typhimurium infection. J. Exp. Med. 203:21–26PubMedCrossRefGoogle Scholar
  93. 93.
    Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258PubMedCrossRefGoogle Scholar
  94. 94.
    Yuki Y, Kiyono H (2003) New generation of mucosal adjuvants for the induction of protective immunity. Rev. Med. Virol. 13:293–310PubMedCrossRefGoogle Scholar
  95. 95.
    Nochi T, Yuki Y, Matsumura A, Mejima M, Terahara K, Kim DY, Fukuyama S, Iwatsuki-Horimoto K, Kawaoka Y, Kohda T, Kozaki S, Igarashi O, Kiyono H (2007) A novel M cell-specific carbohydrate-targeted mucosal vaccine effectively induces antigen-specific immune responses. J. Exp. Med. 204:2789–2796PubMedCrossRefGoogle Scholar
  96. 96.
    Kim PH, Kagnoff MF (1990) Transforming growth factor-β1 is a costimulator for IgA production. J. Immunol. 144:3411–3416PubMedGoogle Scholar
  97. 97.
    Coffman RL, Lebman DA, Shrader B (1989) Transforming growth factor β specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J. Exp. Med. 170:1039–1044PubMedCrossRefGoogle Scholar
  98. 98.
    Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563PubMedCrossRefGoogle Scholar
  99. 99.
    Shikina T, Hiroi T, Iwatani K, Jang MH, Fukuyama S, Tamura M, Kubo T, Ishikawa H, Kiyono H (2004) IgA class switch occurs in the organized nasopharynx- and gut-associated lymphoid tissue, but not in the diffuse lamina propria of airways and gut. J. Immunol. 172:6259–6264PubMedGoogle Scholar
  100. 100.
    Sato A, Hashiguchi M, Toda E, Iwasaki A, Hachimura S, Kaminogawa S (2003) CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. J. Immunol. 171:3684–3690PubMedGoogle Scholar
  101. 101.
    Tezuka H, Abe Y, Iwata M, Takeuchi H, Ishikawa H, Matsushita M, Shiohara T, Akira S, Ohteki T (2007) Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature (Lond) 448:929–933PubMedCrossRefGoogle Scholar
  102. 102.
    Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3:822–829PubMedCrossRefGoogle Scholar
  103. 103.
    Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, Bram RJ, Jabara H, Geha RS (2005) TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201:35–39PubMedCrossRefGoogle Scholar
  104. 104.
    Kwa SF, Beverley P, Smith AL (2006) Peyer's patches are required for the induction of rapid Th1 responses in the gut and mesenteric lymph nodes during an enteric infection. J. Immunol. 176:7533–7541PubMedGoogle Scholar
  105. 105.
    Wang C, McDonald KG, McDonough JS, Newberry RD (2006) Murine isolated lymphoid follicles contain follicular B lymphocytes with a mucosal phenotype. Am. J. Physiol. Gastrointest. Liver Physiol. 291:G595–G604PubMedCrossRefGoogle Scholar
  106. 106.
    Glaysher BR, Mabbott NA (2007) Isolated lymphoid follicle maturation induces the development of follicular dendritic cells. Immunology 120:336–344PubMedCrossRefGoogle Scholar
  107. 107.
    Yamamoto M, Kweon MN, Rennert PD, Hiroi T, Fujihashi K, McGhee JR, Kiyono H (2004) Role of gut-associated lymphoreticular tissues in antigen-specific intestinal IgA immunity. J. Immunol. 173:762–769PubMedGoogle Scholar
  108. 108.
    Kunkel EJ, Butcher EC (2003) Plasma-cell homing. Nat. Rev. Immunol. 3:822–829PubMedCrossRefGoogle Scholar
  109. 109.
    Kunkel EJ, Kim CH, Lazarus NH, Vierra MA, Soler D, Bowman EP, Butcher EC (2003) CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Invest. 111:1001–1010PubMedGoogle Scholar
  110. 110.
    Pan J, Kunkel EJ, Gosslar U, Lazarus N, Langdon P, Broadwell K, Vierra MA, Genovese MC, Butcher EC, Soler D (2000) A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J. Immunol. 165:2943–2949PubMedGoogle Scholar
  111. 111.
    Lazarus NH, Kunkel EJ, Johnston B, Wilson E, Youngman KR, Butcher EC (2003) A common mucosal chemokine (mucosae-associated epithelial chemokine/CCL28) selectively attracts IgA plasmablasts. J. Immunol. 170:3799–3805PubMedGoogle Scholar
  112. 112.
    Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH (2003) Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature (Lond) 424:88–93.CrossRefGoogle Scholar
  113. 113.
    Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538PubMedCrossRefGoogle Scholar
  114. 114.
    Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH (2006) Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314:1157–1160PubMedCrossRefGoogle Scholar
  115. 115.
    Jang MH, Kweon MN, Iwatani K, Yamamoto M, Terahara K, Sasakawa C, Suzuki T, Nochi T, Yokota Y, Rennert PD, Hiroi T, Tamagawa H, Iijima H, Kunisawa J, Yuki Y, Kiyono H (2004) Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl. Acad. Sci. U.S.A. 101:6110–6115PubMedCrossRefGoogle Scholar
  116. 116.
    Chieppa M, Rescigno M, Huang AY, Germain RN (2006) Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203:2841–2852PubMedCrossRefGoogle Scholar
  117. 117.
    Vazquez-Torres A, Jones-Carson J, Baumler AJ, Falkow S, Valdivia R, Brown W, Le M, Berggren R, Parks WT, Fang FC (1999) Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature (Lond) 401:804–808CrossRefGoogle Scholar
  118. 118.
    Hashizume T, Togawa A, Nochi T, Igarashi O, Kweon MN, Kiyono H, Yamamoto M (2008) Peyer's patches are required for intestinal immunoglobulin A responses to Salmonella spp. Infect. Immun. 76:927–934PubMedCrossRefGoogle Scholar
  119. 119.
    Yamamoto M, Rennert P, McGhee JR, Kweon MN, Yamamoto S, Dohi T, Otake S, Bluethmann H, Fujihashi K, Kiyono H (2000) Alternate mucosal immune system: organized Peyer's patches are not required for IgA responses in the gastrointestinal tract. J. Immunol. 164:5184–5191PubMedGoogle Scholar
  120. 120.
    Kang HS, Chin RK, Wang Y, Yu P, Wang J, Newell KA, Fu YX (2002) Signaling via LTβR on the lamina propria stromal cells of the gut is required for IgA production. Nat. Immunol. 3:576–582PubMedCrossRefGoogle Scholar
  121. 121.
    Hiroi T, Yanagita M, Ohta N, Sakaue G, Kiyono H (2000) IL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses. J. Immunol. 165:4329–4337PubMedGoogle Scholar
  122. 122.
    Suzuki K, Meek B, Doi Y, Honjo T, Fagarasan S (2005) Two distinctive pathways for recruitment of naive and primed IgM+ B cells to the gut lamina propria. Proc. Natl. Acad. Sci. U.S.A. 102:2482–2486PubMedCrossRefGoogle Scholar
  123. 123.
    Kunisawa J, Kurashima Y, Gohda M, Higuchi M, Ishikawa I, Miura F, Ogahara I, Kiyono H (2007) Sphingosine 1-phosphate regulates peritoneal B-cell trafficking for subsequent intestinal IgA production. Blood 109:3749–3756PubMedCrossRefGoogle Scholar
  124. 124.
    Wang JR, Stinson MW (1994) Streptococcal M6 protein binds to fucose-containing glycoproteins on cultured human epithelial cells. Infect. Immun. 62:1268–1274PubMedGoogle Scholar
  125. 125.
    Helander A, Silvey KJ, Mantis NJ, Hutchings AB, Chandran K, Lucas WT, Nibert ML, Neutra MR (2003) The viral σ1 protein and glycoconjugates containing β2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces. J. Virol. 77:7964–7977PubMedCrossRefGoogle Scholar
  126. 126.
    Wu Y, Wang X, Csencsits KL, Haddad A, Walters N, Pascual DW (2001) M cell-targeted DNA vaccination. Proc. Natl. Acad. Sci. U.S.A. 98:9318–9323PubMedCrossRefGoogle Scholar
  127. 127.
    Wang X, Hone DM, Haddad A, Shata MT, Pascual DW (2003) M cell DNA vaccination for CTL immunity to HIV. J. Immunol. 171:4717–4725PubMedGoogle Scholar
  128. 128.
    Yuki Y, Hara-Yakoyama C, Guadiz AA, Udaka S, Kiyono H, Chatterjee S (2005) Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetes. Biotechnol. Bioeng. 92:803–809PubMedCrossRefGoogle Scholar
  129. 129.
    Ohmura-Hoshino M, Yamamoto M, Yuki Y, Takeda Y, Kiyono H (2004) Non-toxic Stx derivatives from Escherichia coli possess adjuvant activity for mucosal immunity. Vaccine 22:3751–3761PubMedCrossRefGoogle Scholar
  130. 130.
    Hiroi T, Iwatani K, Iijima H, Kodama S, Yanagita M, Kiyono H (1998) Nasal immune system: distinctive Th0 and Th1/Th2 type environments in murine nasal-associated lymphoid tissues and nasal passage, respectively. Eur. J. Immunol. 28:3346–3353PubMedCrossRefGoogle Scholar
  131. 131.
    Yanagita M, Hiroi T, Kitagaki N, Hamada S, Ito HO, Shimauchi H, Murakami S, Okada H, Kiyono H (1999) Nasopharyngeal-associated lymphoreticular tissue (NALT) immunity: fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachment to epithelial cells and subsequent inflammatory cytokine production. J. Immunol. 162:3559–3565PubMedGoogle Scholar
  132. 132.
    Hiroi T, Goto H, Someya K, Yanagita M, Honda M, Yamanaka N, Kiyono H (2001) HIV mucosal vaccine: nasal immunization with rBCG-V3J1 induces a long term V3J1 peptide-specific neutralizing immunity in Th1- and Th2-deficient conditions. J. Immunol. 167:5862–5867PubMedGoogle Scholar
  133. 133.
    Kurono Y, Shimamura K, Shigemi H, Mogi G (1991) Inhibition of bacterial adherence by nasopharyngeal secretions. Ann. Otol. Rhinol. Laryngol. 100:455–458PubMedGoogle Scholar
  134. 134.
    Kurono Y, Yamamoto M, Fujihashi K, Kodama S, Suzuki M, Mogi G, McGhee JR, Kiyono H (1999) Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity. J. Infect. Dis. 180:122–132PubMedCrossRefGoogle Scholar
  135. 135.
    Harnett W, Harnett MM (1999) Phosphorylcholine: friend or foe of the immune system? Immunol. Today 20:125–129Google Scholar
  136. 136.
    Cundell DR, Gerard NP, Gerard C, Idanpaan-Heikkila I, Tuomanen EI (1995) Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature (Lond) 377:435–438CrossRefGoogle Scholar
  137. 137.
    Tanaka N, Fukuyama S, Fukuiwa T, Kawabata M, Sagara Y, Ito HO, Miwa Y, Nagatake T, Kiyono H, Kurono Y (2007) Intranasal immunization with phosphorylcholine induces antigen specific mucosal and systemic immune responses in mice. Vaccine 25:2680–2687PubMedCrossRefGoogle Scholar
  138. 138.
    Shimoda M, Nakamura T, Takahashi Y, Asanuma H, Tamura S, Kurata T, Mizuochi T, Azuma N, Kanno C, Takemori T (2001) Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue. J. Exp. Med. 194:1597–1607PubMedCrossRefGoogle Scholar
  139. 139.
    Zuercher AW, Coffin SE, Thurnheer MC, Fundova P, Cebra JJ (2002) Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses. J. Immunol. 168:1796–1803PubMedGoogle Scholar
  140. 140.
    Sakaue G, Hiroi T, Nakagawa Y, Someya K, Iwatani K, Sawa Y, Takahashi H, Honda M, Kunisawa J, Kiyono H (2003) HIV mucosal vaccine: nasal immunization with gp160-encapsulated hemagglutinating virus of Japan-liposome induces antigen-specific CTLs and neutralizing antibody responses. J. Immunol. 170:495–502.PubMedGoogle Scholar
  141. 141.
    Lazarus NH, Kunkel EJ, Johnston B, Wilson E, Youngman KR, Butcher EC (2003) A common mucosal chemokine (mucosae-associated epithelial chemokine/CCL28) selectively attracts IgA plasmablasts. J. Immunol. 170:3799–3805PubMedGoogle Scholar
  142. 142.
    Teitelbaum R, Schubert W, Gunther L, Kress Y, Macaluso F, Pollard JW, McMurray DN, Bloom BR (1999) The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis. Immunity 10:641–650PubMedCrossRefGoogle Scholar
  143. 143.
    Soerensen CM, Holmskov U, Aalbaek B, Boye M, Heegaard PM, Nielsen OL (2005) Pulmonary infections in swine induce altered porcine surfactant protein D expression and localization to dendritic cells in bronchial-associated lymphoid tissue. Immunology 115:526–535PubMedCrossRefGoogle Scholar
  144. 144.
    Suda T, Chida K, Hayakawa H, Imokawa S, Iwata M, Nakamura H, Sato A (1999) Development of bronchus-associated lymphoid tissue in chronic hypersensitivity pneumoni-tis. Chest 115:357–363PubMedCrossRefGoogle Scholar
  145. 145.
    Hikono H, Kohlmeier JE, Ely KH, Scott I, Roberts AD, Blackman MA, Woodland DL (2006) T-cell memory and recall responses to respiratory virus infections. Immunol. Rev. 211:119–132PubMedCrossRefGoogle Scholar
  146. 146.
    Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K, Morii E, Aozasa K, Kawai T, Akira S (2007) Alveolar macrophages are the primary interferon-α producer in pulmonary infection with RNA viruses. Immunity 27:240–252PubMedCrossRefGoogle Scholar
  147. 147.
    Min SY, Park KS, Cho ML, Kang JW, Cho YG, Hwang SY, Park MJ, Yoon CH, Min JK, Lee SH, Park SH, Kim HY (2006) Antigen-induced, tolerogenic CD11c+, CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis. Arthritis Rheum. 54:887–898PubMedCrossRefGoogle Scholar
  148. 148.
    Sun JB, Raghavan S, Sjoling A, Lundin S, Holmgren J (2006) Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+CD25+ and Foxp3CD25 CD4+ regulatory T cells. J. Immunol. 177:7634–7644PubMedGoogle Scholar
  149. 149.
    Seino K, Taniguchi M (2004) Functional roles of NKT cell in the immune system. Front. Biosci. 9:2577–2587PubMedCrossRefGoogle Scholar
  150. 150.
    Lisbonne M, Diem S, de Castro Keller A, Lefort J, Araujo LM, Hachem P, Fourneau JM, Sidobre S, Kronenberg M, Taniguchi M, Van Endert P, Dy M, Askenase P, Russo M, Vargaftig BB, Herbelin A, Leite-de-Moraes MC (2003) Cutting edge: invariant Vα14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol. 171:1637–1641PubMedGoogle Scholar
  151. 151.
    Kim HJ, Hwang SJ, Kim BK, Jung KC, Chung DH (2006) NKT cells play critical roles in the induction of oral tolerance by inducing regulatory T cells producing IL-10 and transforming growth factor β, and by clonally deleting antigen-specific T cells. Immunology 118:101–111PubMedCrossRefGoogle Scholar
  152. 152.
    Fujihashi K, Dohi T, Rennert PD, Yamamoto M, Koga T, Kiyono H, McGhee JR (2001) Peyer's patches are required for oral tolerance to proteins. Proc. Natl. Acad. Sci. U.S.A. 98:3310–3315PubMedCrossRefGoogle Scholar
  153. 153.
    Spahn TW, Fontana A, Faria AM, Slavin AJ, Eugster HP, Zhang X, Koni PA, Ruddle NH, Flavell RA, Rennert PD, Weiner HL (2001) Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches. Eur. J. Immunol. 31:1278–1287PubMedCrossRefGoogle Scholar
  154. 154.
    Kraus TA, Brimnes J, Muong C, Liu JH, Moran TM, Tappenden KA, Boros P, Mayer L (2005) Induction of mucosal tolerance in Peyer's patch-deficient, ligated small bowel loops. J. Clin. Invest. 115:2234–2243PubMedCrossRefGoogle Scholar
  155. 155.
    Bilsborough J, George TC, Norment A, Viney JL (2003) Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108:481–492PubMedCrossRefGoogle Scholar
  156. 156.
    Spahn TW, Weiner HL, Rennert PD, Lugering N, Fontana A, Domschke W, Kucharzik T (2002) Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyer's patches. Eur. J. Immunol. 32:1109–1113PubMedCrossRefGoogle Scholar
  157. 157.
    Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria mac-rophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8:1086–1094PubMedCrossRefGoogle Scholar
  158. 158.
    Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Curr. Opin. Immunol. 19:652–657PubMedCrossRefGoogle Scholar
  159. 159.
    Mahida YR (2000) The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm. Bowel Dis. 6:21–33PubMedGoogle Scholar
  160. 160.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204:1775–1785PubMedCrossRefGoogle Scholar
  161. 161.
    Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204:1757–1764PubMedCrossRefGoogle Scholar
  162. 162.
    Wolvers DA, Coenen-de Roo CJ, Mebius RE, van der Cammen MJ, Tirion F, Miltenburg AM, Kraal G (1999) Intranasally induced immunological tolerance is determined by characteristics of the draining lymph nodes: studies with OVA and human cartilage gp-39. J. Immunol. 162:1994–1998PubMedGoogle Scholar
  163. 163.
    Unger WW, Hauet-Broere F, Jansen W, van Berkel LA, Kraal G, Samsom JN (2003) Early events in peripheral regulatory T cell induction via the nasal mucosa. J. Immunol. 171:4592–4603PubMedGoogle Scholar
  164. 164.
    Samsom JN, van Berkel LA, van Helvoort JM, Unger WW, Jansen W, Thepen T, Mebius RE, Verbeek SS, Kraal G (2005) FcγRIIB regulates nasal and oral tolerance: a role for dendritic cells. J. Immunol. 174:5279–5287PubMedGoogle Scholar
  165. 165.
    van der Marel AP, Samsom JN, Greuter M, van Berkel LA, O'Toole T, Kraal G, Mebius RE (2007) Blockade of IDO inhibits nasal tolerance induction. J. Immunol. 179:894–900PubMedGoogle Scholar
  166. 166.
    Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4:762–774PubMedCrossRefGoogle Scholar
  167. 167.
    Rharbaoui F, Bruder D, Vidakovic M, Ebensen T, Buer J, Guzman CA (2005) Characterization of a B220+ lymphoid cell subpopulation with immune modulatory functions in nasal-associated lymphoid tissues. J. Immunol. 174:1317–1324PubMedGoogle Scholar
  168. 168.
    Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat. Rev. Immunol. 8:205–217PubMedCrossRefGoogle Scholar
  169. 169.
    Kweon MN, Yamamoto M, Kajiki M, Takahashi I, Kiyono H (2000) Systemically derived large intestinal CD4+ Th2 cells play a central role in STAT6-mediated allergic diarrhea. J. Clin. Invest. 106:199–206PubMedCrossRefGoogle Scholar
  170. 170.
    Hino A, Fukuyama S, Kataoka K, Kweon MN, Fujihashi K, Kiyono H (2005) Nasal IL-12p70 DNA prevents and treats intestinal allergic diarrhea. J. Immunol. 174:7423–7432PubMedGoogle Scholar
  171. 171.
    Takayama N, Igarashi O, Kweon MN, Kiyono H (2007) Regulatory role of Peyer's patches for the inhibition of OVA-induced allergic diarrhea. Clin. Immunol. 123:199–208PubMedCrossRefGoogle Scholar
  172. 172.
    Yamashita N, Tashimo H, Matsuo Y, Ishida H, Yoshiura K, Sato K, Yamashita N, Kakiuchi T, Ohta K (2006) Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model. J. Allergy Clin. Immunol. 117:1040–1046PubMedCrossRefGoogle Scholar
  173. 173.
    Kusters JG, van Vliet AH, Kuipers EJ (2006) Pathogenesis of Helicobacter pylori infection. Clin. Microbiol. Rev. 19:449–490PubMedCrossRefGoogle Scholar
  174. 174.
    Nagai S, Mimuro H, Yamada T, Baba Y, Moro K, Nochi T, Kiyono H, Suzuki T, Sasakawa C, Koyasu S (2007) Role of Peyer's patches in the induction of Helicobacter pylori-induced gastritis. Proc. Natl. Acad. Sci. U.S.A. 104:8971–8976PubMedCrossRefGoogle Scholar
  175. 175.
    Dohi T, Rennert PD, Fujihashi K, Kiyono H, Shirai Y, Kawamura YI, Browning JL, McGhee JR (2001) Elimination of colonic patches with lymphotoxin β receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167:2781–2790PubMedGoogle Scholar
  176. 176.
    Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, Hamada H, Asakura H, Ishikawa H, Matsushima K (2003) Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat. Immunol. 4:154–160PubMedCrossRefGoogle Scholar
  177. 177.
    Welniak LA, Kuprash DV, Tumanov AV, Panoskaltsis-Mortari A, Blazar BR, Sun K, Nedospasov SA, Murphy WJ (2006) Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation. Blood 107:410–412PubMedCrossRefGoogle Scholar
  178. 178.
    Xie Y, Chen X, Nishi S, Narita I, Gejyo F (2004) Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy. Kidney Int. 65:1135–1144PubMedCrossRefGoogle Scholar
  179. 179.
    Kerakawauchi H, Kurono Y, Mogi G (1997) Immune responses against Streptococcus pyo-genes in human palatine tonsils. Laryngoscope 107:634–639PubMedCrossRefGoogle Scholar
  180. 180.
    Boyaka PN, Wright PF, Marinaro M, Kiyono H, Johnson JE, Gonzales RA, Ikizler MR, Werkhaven JA, Jackson RJ, Fujihashi K, Di Fabio S, Staats HF, McGhee JR (2000) Human nasopharyngeal-associated lymphoreticular tissues. Functional analysis of subepithelial and intraepithelial B and T cells from adenoids and tonsils. Am. J. Pathol. 157:2023–2035Google Scholar
  181. 181.
    Tokuda M, Shimizu J, Sugiyama N, Kiryu T, Matsuoka K, Sasaki O, Fukuda K, Hatase O, Monden H (1996) Direct evidence of the production of IgA by tonsillar lymphocytes and the binding of IgA to the glomerular mesangium of IgA nephropathy patients. Acta Otolaryngol. Suppl. 523:182–184PubMedGoogle Scholar
  182. 182.
    Narita I, Gejyo F (2008) Pathogenetic significance of aberrant glycosylation of IgA1 in IgA nephropathy. Clin. Exp. Nephrol. 12(5):1342–1751CrossRefGoogle Scholar
  183. 183.
    Nishi S, Xie Y, Ueno M, Imai N, Suzuki Y, Iguchi S, Fukase S, Mori H, Alchi B, Shimada H, Arakawa M, Gejyo F (2004) A clinicopathological study on the long-term efficacy of tonsillectomy in patients with IgA nephropathy. Acta Otolaryngol. Suppl. 555:49–53PubMedCrossRefGoogle Scholar
  184. 184.
    Kawano M, Okada K, Muramoto H, Morishita H, Omura T, Inoue R, Kitajima S, Katano K, Koni I, Mabuchi H, Yachie A (2003) Simultaneous, clonally identical T cell expansion in tonsil and synovium in a patient with rheumatoid arthritis and chronic tonsillitis. Arthritis Rheum. 48:2483–2488PubMedCrossRefGoogle Scholar
  185. 185.
    Noda K, Kodama S, Suenaga S, Suzuki M (2007) Tonsillar focal infectious disease involving IgA nephropathy, pustulosis, and ossification. Clin. Exp. Nephrol. 11:97–101PubMedCrossRefGoogle Scholar
  186. 186.
    Goodarzi H, Trowbridge J, Gallo RL (2007) Innate immunity: a cutaneous perspective. Clin. Rev. Allergy Immunol. 33:15–26PubMedCrossRefGoogle Scholar
  187. 187.
    Glenn GM, Scharton-Kersten T, Vassell R, Mallett CP, Hale TL, Alving CR (1998) Transcutaneous immunization with cholera toxin protects mice against lethal mucosal toxin challenge. J. Immunol. 161:3211–3214PubMedGoogle Scholar
  188. 188.
    Etchart N, Hennino A, Friede M, Dahel K, Dupouy M, Goujon-Henry C, Nicolas JF, Kaiserlian D (2007) Safety and efficacy of transcutaneous vaccination using a patch with the live-attenuated measles vaccine in humans. Vaccine 25:6891–6899PubMedCrossRefGoogle Scholar
  189. 189.
    Berry LJ, Hickey DK, Skelding KA, Bao S, Rendina AM, Hansbro PM, Gockel CM, Beagley KW (2004) Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect. Immun. 72:1019–1028PubMedCrossRefGoogle Scholar
  190. 190.
    Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, Kobayashi M, Sakabe JI, Yoshiki R, Tamamura H, Fujii N, Inaba K, Tokura Y (2007) CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am. J. Pathol. 171:1249–1257PubMedCrossRefGoogle Scholar
  191. 191.
    Chang SY, Cha HR, Igarashi O, Rennert PD, Kissenpfennig A, Malissen B, Nanno M, Kiyono H, Kweon MN (2008) Cutting edge: langerin+ dendritic cells in the mesenteric lymph node set the stage for skin and gut immune system cross-talk. J. Immunol. 180:4361–4365PubMedGoogle Scholar
  192. 192.
    Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA (2004) New insights into atopic dermatitis. J. Clin. Invest. 113:651–657PubMedGoogle Scholar
  193. 193.
    Nikkels AF, Pierard GE (2003) Framing the future of antifungals in atopic dermatitis. Dermatology 206:398–400PubMedCrossRefGoogle Scholar
  194. 194.
    Suenobu N, Kweon MN, Kiyono H (2002) Nasal vaccination induces the ability to eliminate Candida colonization without influencing the pre-existing antigen-specific IgE Abs: a possibility for the control of Candida-related atopic dermatitis. Vaccine 20:2972–2980PubMedCrossRefGoogle Scholar
  195. 195.
    Prescott SL, Björkstén B (2007) Probiotics for the prevention or treatment of allergic diseases. J. Allergy Clin. Immunol. 120:255–262PubMedCrossRefGoogle Scholar
  196. 196.
    Sawada J, Morita H, Tanaka A, Salminen S, He F, Matsuda H (2007) Ingestion of heat-treated Lactobacillus rhamnosus GG prevents development of atopic dermatitis in NC/Nga mice. Clin. Exp. Allergy 37:296–303PubMedCrossRefGoogle Scholar
  197. 197.
    Hayashi Y, Kunimoto M, Kuki K, Yamanaka N (1996) Animal model of focal tonsillar infection: human tonsillar lymphocytes induce skin lesion in SCID mice. Acta Otolaryngol. Suppl. 523:193–196PubMedGoogle Scholar
  198. 198.
    Nozawa H, Kishibe K, Takahara M, Harabuchi Y (2005) Expression of cutaneous lymphocyte-associated antigen (CLA) in tonsillar T-cells and its induction by in vitro stimulation with alpha-streptococci in patients with pustulosis palmaris et plantaris (PPP). Clin. Immunol. 116:42–53PubMedCrossRefGoogle Scholar
  199. 199.
    Shiraishi S, Tomoda K, Matsumoto A, Kyomoto R, Yamashita T (1996) Investigation of the local provocation test to PPP and IgA nephritis. Acta Otolaryngol. Suppl. 523:178–181PubMedGoogle Scholar
  200. 200.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260PubMedCrossRefGoogle Scholar
  201. 201.
    Nochi T, Takagi H, Yuki Y, Yang L, Masumura T, Mejima M, Nakanishi U, Matsumura A, Uozumi A, Hiroi T, Morita S, Tanaka K, Takaiwa F, Kiyono H (2007) From the Cover: Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination. Proc. Natl. Acad. Sci. U.S.A. 104:10986–10991PubMedCrossRefGoogle Scholar
  202. 202.
    Takagi H, Hiroi T, Yang L, Tada Y, Yuki Y, Takamura K, Ishimitsu R, Kawauchi H, Kiyono H, Takaiwa F (2005) A rice-based edible vaccine expressing multiple T cell epitopes induces oral tolerance for inhibition of Th2-mediated IgE responses. Proc. Natl. Acad. Sci. U.S.A. 102:17525–17530PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Satoshi Fukuyama
    • 1
    • 2
  • Takahiro Nagatake
    • 1
  • Hiroshi Kiyono
    • 1
  1. 1.Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical ScienceThe University of TokyoMinato-kuJapan
  2. 2.Division of Molecular ImmunologyLa Jolla Institute for Allergy and ImmunologyLa JollaUSA

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