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Mucosal Immunity: from Allergy to Coeliac Disease

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Allergy Frontiers: Classification and Pathomechanisms

Part of the book series: Allergy Frontiers ((ALLERGY,volume 2))

During evolution, the mucosal immune system has developed two homeostatic mechanisms: (i) immune exclusion mediated by secretory antibodies to control epithelial colonization of microorganisms and inhibit penetration of potentially dangerous substances; and (ii) immunosuppression to counteract hypersensitivity against innocuous antigens such as allergens and most food proteins. The latter mechanism is referred to as ‘oral tolerance’ when induced via the gut. Similar down-regulatory mechanisms apparently operate against components of the commensal microbiota. This two-layered anti-inflammatory preservation of mucosal integrity probably explains why overt and persistent allergy to dietary proteins is not more common, with the exception of gluten-intolerance (coeliac disease), where abrogation of mucosal homeostasis becomes apparent.

Overall, mucosally induced oral tolerance is a robust adaptive mechanism in view of the fact that a ton of food may pass annually through the gut of an adult ? regularly resulting in uptake of some intact dietary antigens. However, the immunoregulatory network and the epithelial barrier function are poorly developed for a variable period after birth. The neonatal period is therefore critical with regard to priming for allergy. Notably, the postnatal development of mucosal immune homeostasis depends on appropriate microbial colonization. In this process, dendritic antigen-presenting cells are ‘decision makers’ ? linking innate and adaptive immunity; their function is influenced by both microbial products and dietary constituents, including vitamin A and lipids such as polyunsaturated -3 fatty acids.

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References

  1. Bruijnzeel-Koomen C, Ortolani C, Aas K, Bindslev-Jensen C, Björksten B, Moneret-Vautrin D, Wuthrich B. Adverse reactions to food. European Academy of Allergology and Clinical Immunology Subcommittee. Allergy 1995; 50:623–635.

    Article  PubMed  CAS  Google Scholar 

  2. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, Kowalski ML, Mygind N, Ring J, van Cauwenberge P, van Hage-Hamsten M, Wüthrich B. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001; 56:813–824.

    Article  PubMed  CAS  Google Scholar 

  3. Brandtzaeg P. Mechanisms of gastrointestinal reactions to food. Environ Toxicol Pharmacol 1997; 4:9–24.

    Article  CAS  Google Scholar 

  4. Brandtzaeg P. The changing immunological paradigm in coeliac disease. Immunol Lett 2006; 105:127–139.

    Article  PubMed  CAS  Google Scholar 

  5. Bischoff SC, Mayer JH, Manns M P. Allergy and the gut. Int Arch Allergy Immunol 2000;121: 270–283.

    Article  PubMed  CAS  Google Scholar 

  6. Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E. Cytokines and adhesion molecules in duodenal mucosa of children with delayed-type food allergy. J Pediatr Gastroenterol Nutr 2003;37:27–34.

    Article  PubMed  CAS  Google Scholar 

  7. Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K. Cow's milk allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy 1999; 54:346–351.

    Article  PubMed  CAS  Google Scholar 

  8. Knutson TW, Bengtsson U, Dannaeus A, Ahlstedt S, Stalenheim G, Hällgren R, Knutson L. Intestinal reactivity in allergic and nonallergic patients: an approach to determine the complexity of the mucosal reaction. J Allergy Clin Immunol 1993; 91:553–559.

    Article  PubMed  CAS  Google Scholar 

  9. Bengtsson U, Knutson TW, Knutson L, Dannaeus A, Hällgren R, Ahlstedt S. Increased levels of hyaluronan and albumin after intestinal challenge in adult patients with cow's milk intolerance. Clin Exp Allergy 1996; 26:96–103.

    Article  PubMed  CAS  Google Scholar 

  10. Bengtsson U, Knutson TW, Knutson L, Dannaeus A, Hällgren R, Ahlstedt S. Eosinophil cationic protein and histamine after intestinal challenge in patients with cow's milk intolerance. J Allergy Clin Immunol 1997; 100:216–221.

    Article  PubMed  CAS  Google Scholar 

  11. Lin XP, Magnusson J, Ahlstedt S, Dahlman-Höglund A, Hanson LÅ, Magnusson O, Bengtsson U, Telemo E. Local allergic reaction in food-hypersensitive adults despite a lack of systemic food-specific IgE. J Allergy Clin Immunol 2002; 109:879–887.

    Article  PubMed  Google Scholar 

  12. Brandtzaeg P. History of oral tolerance and mucosal immunity. Ann NY Acad Sci 1996; 778:1–27.

    Article  PubMed  CAS  Google Scholar 

  13. Duchmann R, Neurath M, Marker-Hermann E, Meyer Zum Buschenfelde KH. Immune responses towards intestinal bacteria—current concepts and future perspectives. Zeitschr Gastroenterol 1997; 35:337–346.

    CAS  Google Scholar 

  14. Karlsson MR, Kahu H, Hanson LÅ, Telemo E, Dahlgren UI. Neonatal colonization of rats induces immunological tolerance to bacterial antigens. Eur J Immunol 1999; 29:109–118.

    Article  PubMed  CAS  Google Scholar 

  15. Helgeland L, Brandtzaeg P. Development and function of intestinal B and T cells. Microbiol Ecol Health Dis 2000; 12(Suppl 2):110–127.

    Article  Google Scholar 

  16. Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy 2000; 55:688–697.

    Article  PubMed  CAS  Google Scholar 

  17. Brandtzaeg P, Nilssen DE, Rognum TO, Thrane PS. Ontogeny of the mucosal immune system and IgA deficiency. Gastroenterol Clin North Am 1991; 20:397–439.

    PubMed  CAS  Google Scholar 

  18. Holt PG. Postnatal maturation of immune competence during infancy and childhood. Pediatr Allergy Immunol 1995; 6:59–70.

    Article  PubMed  CAS  Google Scholar 

  19. Brandtzaeg P. Development of the mucosal immune system in humans. In: Recent Developments in Infant Nutrition (Eds.: Bindels JG, Goedhart AC, Visser HKA). Kluwer, London, 1996; 349–376.

    Google Scholar 

  20. Brandtzaeg P. Development and basic mechanisms of human gut immunity. Nutr Rev 1998; 56:S5–18.

    PubMed  CAS  Google Scholar 

  21. Moreau MC, Gaboriau-Routhiau V. Immunomodulation by the gut microflora and probiotics. Probiotics 2000; 3:69–114.

    Google Scholar 

  22. Yamanaka T, Helgeland L, Farstad IN, Midtvedt T, Fukushima H, Brandtzaeg P. Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer's patches. J Immunol 2003; 170:816–822.

    PubMed  CAS  Google Scholar 

  23. Brandtzaeg P, Johansen F-E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev 2005; 206:32–63.

    Article  PubMed  CAS  Google Scholar 

  24. Brandtzaeg P. Two types of IgA immunocytes in man. Nature New Biol 1973; 243:142–143.

    PubMed  CAS  Google Scholar 

  25. Brandtzaeg P. Presence of J chain in human immunocytes containing various immunoglobulin classes. Nature 1974; 252:418–420.

    Article  PubMed  CAS  Google Scholar 

  26. Brandtzaeg P. Mucosal and glandular distribution of immunoglobulin components: differential localization of free and bound SC in secretory epithelial cells. J Immunol 1974; 112: 1553–1559.

    PubMed  CAS  Google Scholar 

  27. Brandtzaeg P, Prydz H. Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulin. Nature 1984; 311:71–73.

    Article  PubMed  CAS  Google Scholar 

  28. Johansen F-E, Pekna M, Norderhaug IN, Haneberg B, Hietala MA, Krajci P, Betsholtz C, Brandtzaeg P. Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice. J Exp Med 1999; 190:915–921.

    Article  PubMed  CAS  Google Scholar 

  29. Persson CG, Erjefält JS, Greiff L, Erjefält I, Korsgren M, Linden M, Sundler F, Andersson M, Svensson C. Contribution of plasma-derived molecules to mucosal immune defence, disease and repair in the airways. Scand J Immunol 1998; 47:302–313.

    Article  PubMed  CAS  Google Scholar 

  30. Yoshida M, Claypool SM, Wagner JS, Mizoguchi E, Mizoguchi A, Roopenian DC, Lencer WI, Blumberg RS. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 2004; 20:769–783.

    Article  PubMed  CAS  Google Scholar 

  31. Ogra SS, Weintraub D, Ogra PL. Immunologic aspects of human colostrum and milk. III. Fate and absorption of cellular and soluble components in the gastrointestinal tract of the newborn. J Immunol 1977; 119:245–248.

    PubMed  CAS  Google Scholar 

  32. Klemola T, Savilahti E, Leinikki P. Mumps IgA antibodies are not absorbed from human milk. Acta Paediatr Scand 1986; 75:230–232.

    Article  PubMed  CAS  Google Scholar 

  33. Weaver LT, Wadd N, Taylor CE, Greenwell J, Toms GL. The ontogeny of serum IgA in the newborn. Pediatr Allergy Immunol 1991; 2:2–75.

    Article  Google Scholar 

  34. van Elburg RM, Uil JJ, de Monchy JG, Heymans HS. Intestinal permeability in pediatric gastroenterology. Scand J Gastroenterol 1992; 194 (suppl):19–24.

    Article  Google Scholar 

  35. Sait LC, Galic M, Price JD, Simpfendorfer KR, Diavatopoulos DA, Uren TK, Janssen PH, Wijburg OL, Strugnell RA. Secretory antibodies reduce systemic antibody responses against the gastrointestinal commensal flora. Int Immunol 2007;19:257–265.

    Article  PubMed  CAS  Google Scholar 

  36. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science 2001; 291:881–884.

    Article  PubMed  CAS  Google Scholar 

  37. Neish AS, Gewirtz AT, Zeng H, Young AN, Hobert ME, Karmali V, Rao AS, Madara JL. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 2000; 289:1560–1563.

    Article  PubMed  CAS  Google Scholar 

  38. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118:229–241.

    Article  PubMed  CAS  Google Scholar 

  39. Bambou JC, Giraud A, Menard S, Begue B, Rakotobe S, Heyman M, Taddei F, Cerf-Bensussan N, Gaboriau-Routhiau V. In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J Biol Chem 2004; 279:42984–42992.

    Article  PubMed  CAS  Google Scholar 

  40. Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, Lee HK, Shen C, Cojocaru G, Shenouda S, Kagnoff M, Eckmann L, Ben-Neriah Y, Raz E. Maintenance of colonic home-ostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 2006; 8:1327–1336.

    Article  PubMed  CAS  Google Scholar 

  41. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B, Gumucio D, Neurath MF, Pasparakis M. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007; 446:557–561.

    Article  PubMed  CAS  Google Scholar 

  42. Haller D, Bode C, Hammes WP, Pfeifer AM, Schiffrin EJ, Blum S. Non-pathogenic bacteria elicit a differential cytokine response by intestinal epithelial cell/leucocyte co-cultures. Gut 2000; 47:79–87.

    Article  PubMed  CAS  Google Scholar 

  43. Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, Nespoli A, Viale G, Allavena P, Rescigno M. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 2005; 6:507–514.

    Article  PubMed  CAS  Google Scholar 

  44. Lotz M, Gutle D, Walther S, Menard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203:973–984.

    Article  PubMed  CAS  Google Scholar 

  45. Eggesbø M, Botten G, Stigum H, Nafstad P, Magnus P. Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol 2003; 112:420–426.

    Article  PubMed  Google Scholar 

  46. Brandtzaeg P. Role of local immunity and breast-feeding in mucosal homeostasis and defence against infections. pp. 273–320. In: Nutrition and Immune Function (Eds.: Calder PC, Field CJ, Gill HS). Frontiers in Nutritional Science, No. 1, CAB International, Oxon, UK, 2002.

    Google Scholar 

  47. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J Clin Nutr 2002; 75:914–921.

    PubMed  CAS  Google Scholar 

  48. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LÅ, Høst A, Kuitunen M, Olsen SF, Skerfving S, Sundell J, Wille S. Breastfeeding and allergic disease: a multidisci-plinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 2003; 58:833–843.

    Google Scholar 

  49. Kull I, Wickman M, Lilja G, Nordvall SL, Pershagen G. Breast feeding and allergic diseases in infants-a prospective birth cohort study. Arch Dis Child 2002; 87:478–481.

    Article  PubMed  CAS  Google Scholar 

  50. Schoetzau A, Filipiak-Pittroff B, Franke K, Koletzko S, Vo n Berg A, Gruebl A, Bauer CP, Berdel D, Reinhardt D, Wichmann HE; German Infant Nutritional Intervention Study Group. Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. Pediatr Allergy Immunol 2002; 13: 2342–42.

    Article  Google Scholar 

  51. Kull I, Almqvist C, Lilja G, Pershagen G, Wickman M. Breast-feeding reduces the risk of asthma during the first 4 years of life. J Allergy Clin Immunol 2004; 114:755–760.

    Article  PubMed  Google Scholar 

  52. Kull I, Böhme M, Wahlgren CF, Nordvall L, Pershagen G, Wickman M. Breast-feeding reduces the risk for childhood eczema. J Allergy Clin Immunol 2005; 116:657–661.

    Article  PubMed  Google Scholar 

  53. Benn CS, Wohlfahrt J, Aaby P, Westergaard T, Benfeldt E, Michaelsen KF, Björksten B, Melbye M. Breastfeeding and risk of atopic dermatitis, by parental history of allergy, during the first 18 months of life. Am J Epidemiol 2004; 160:217–223.

    Article  PubMed  Google Scholar 

  54. Savilahti E, Tainio VM, Salmenpera L, Arjomaa P, Kallio M, Perheentupa J, Siimes MA. Low colostral IgA associated with cow's milk allergy. Acta Paediatr Scand 1991; 80:1207–1213.

    Article  PubMed  CAS  Google Scholar 

  55. Järvinen KM, Laine ST, Järvenpää AL, Suomalainen HK. Does low IgA in human milk predispose the infant to development of cow's milk allergy? Pediatr Res 2000; 48:457–462.

    Article  PubMed  Google Scholar 

  56. Field CJ. The immunological components of human milk and their effect on immune development in infants. J Nutr 2005; 135:1–4.

    PubMed  CAS  Google Scholar 

  57. Planchon SM, Martins CA, Guerrant RL, Roche JK. Regulation of intestinal epithelial barrier function by TGF-β1. Evidence for its role in abrogating the effect of a T cell cytokine. J Immunol 1994; 153:5730–5739.

    PubMed  CAS  Google Scholar 

  58. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113:805–19.

    Article  PubMed  CAS  Google Scholar 

  59. Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996; 9:687–695.

    Google Scholar 

  60. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351:1225–1232.

    Article  Google Scholar 

  61. Guarner F, Bourdet-Sicard R, Brandtzaeg P, Gill HS, McGuirk P, van Eden W, Versalovic J, Weinstock JV, Rook GAW. Mechanisms of disease: the hygiene hypothesis revisited. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006; 3:275–284.

    Article  PubMed  CAS  Google Scholar 

  62. Brandtzaeg P. Current understanding of gastrointestinal immunoregulation and its relation to food allergy. Ann NY Acad Sci 2002; 964:13–45.

    PubMed  CAS  Google Scholar 

  63. Rothberg RM, Farr RS. Anti-bovine serum albumine and anti-alpha lactalbumin in the serum of children and adults. Pediatrics 1965; 35:571–588.

    PubMed  CAS  Google Scholar 

  64. Scott H, Rognum TO, Midtvedt T, Brandtzaeg P. Age-related changes of human serum antibodies to dietary and colonic bacterial antigens measured by an enzyme-linked immunosorb-ent assay. Acta Pathol Microbiol Immunol [C] Scand 1985; 93:65–70.

    CAS  Google Scholar 

  65. Korenblat PE, Rothberg RM, Minden P, Farr RS. Immune responses of human adults after oral and parenteral exposure to bovine serum albumin. J Allergy 1968; 41:226–235.

    Article  PubMed  CAS  Google Scholar 

  66. Waldo FB, van den Wall Bake AW, Mestecky J, Husby S. Suppression of the immune response by nasal immunization. Clin Immunol Immunopathol 1994; 72:30–34.

    Article  PubMed  CAS  Google Scholar 

  67. Husby S, Mestecky J, Moldoveanu Z, Holland S, Elson CO. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding. J Immunol 1994; 152:4663–4670.

    PubMed  CAS  Google Scholar 

  68. Kraus TA, Toy L, Chan L, Childs J, Mayer L. Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease. Gastroenterology 2004; 126:1771–1778.

    Article  PubMed  CAS  Google Scholar 

  69. Qiao L, Braunstein J, Golling M, Schurmann G, Autschbach F, Moller P, Meuer S. Differential regulation of human T cell responsiveness by mucosal versus blood monocytes. Eur J Immunol 1996; 26:922–927.

    Article  PubMed  CAS  Google Scholar 

  70. Smith PD, Smythies LE, Mosteller-Barnum M, Sibley DA, Russell MW, Merger M, Sellers MT, Orenstein JM, Shimada T, Graham MF, Kubagawa H. Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol 2001; 167:2651–2656.

    PubMed  CAS  Google Scholar 

  71. Rugtveit J, Nilsen EM, Bakka A, Carlsen H, Brandtzaeg P, Scott H. Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology 1997; 112:1493–1505.

    Article  PubMed  CAS  Google Scholar 

  72. Milling SW, Cousins L, MacPherson GG. How do DCs interact with intestinal antigens? Trends Immunol 2005; 26:349–352.

    Article  PubMed  CAS  Google Scholar 

  73. Mowat AM. Nature Rev Immunol 3: 331–271. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003 3:331–341.

    Article  PubMed  CAS  Google Scholar 

  74. Worbs T, Bode U, Yan S, Hoffmann MW, Hintzen G, Bernhardt G, Forster R, Pabst O. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med 2006; 203:519–527.

    Article  PubMed  CAS  Google Scholar 

  75. Holt PG. Pulmonary dendritic cells in local immunity to inert and pathogenic antigens in the respiratory tract. Proc Am Thorac Soc 2005; 2:116–120.

    Article  PubMed  CAS  Google Scholar 

  76. Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 2005; 115:66–75.

    PubMed  CAS  Google Scholar 

  77. Macpherson AJ, Geuking MB, McCoy KD. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005; 115:153–162.

    Article  PubMed  CAS  Google Scholar 

  78. Strauch UG, Obermeier F, Grunwald N, Gurster S, Dunger N, Schultz M, Griese DP, Mahler M, Scholmerich J, Rath HC. Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis. Gut 2005; 54:1546–1552.

    Article  PubMed  CAS  Google Scholar 

  79. Weinstock JV, Summers R, Elliott DE. Helminths and harmony. Gut 2004; 53:7–9.

    Article  PubMed  CAS  Google Scholar 

  80. Wilson MS, Taylor MD, Balic A, Finney CA, Lamb JR, Maizels RM. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 2005; 202:1199–1212.

    Article  PubMed  CAS  Google Scholar 

  81. Blümer N, Herz U, Wegmann M, Renz H. Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 2005; 35:397–402.

    Article  PubMed  CAS  Google Scholar 

  82. Gerhold K, Avagyan A, Seib C, Frei R, Steinle J, Ahrens B, Dittrich AM, Blumchen K, Lauener R, Hamelmann E. Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol 2006; 118:666–673.

    Article  PubMed  CAS  Google Scholar 

  83. Eder W, von Mutius E. Genetics in asthma: the solution to a lasting conundrum? Allergy 2005; 60:1482–1484.

    Article  PubMed  CAS  Google Scholar 

  84. Jones G. Susceptibility to asthma and eczema from mucosal and epidermal expression of distinctive genes. Curr Allergy Asthma Rep 2007; 7:11–17.

    Article  PubMed  CAS  Google Scholar 

  85. Rautava S, Ruuskanen O, Ouwehand A, Salminen S, Isolauri E. The hygiene hypothesis of atopic disease—an extended version. J Pediatr Gastroenterol Nutr 2004; 38:378–388.

    Article  PubMed  Google Scholar 

  86. Sanders ME, Guarner F, Mills D, Pot B, Rafter J, Rastall B, Reid G, Ringel Y, Rowland I, Saarela M, Tuohy K. Selected topics in probiotics and prebiotics: meeting report for the 2004 International Scientific Association for Probiotics and prebiotics. Curr Issues Intest Microbiol 2005; 6:55–68.

    PubMed  Google Scholar 

  87. Moreels TG, Pelckmans PA. Gastrointestinal parasites: potential therapy for refractory inflammatory bowel diseases. Inflamm Bowel Dis 2005; 11:178–184.

    Article  PubMed  Google Scholar 

  88. Kaila M, Isolauri E, Soppi E, Virtanen E, Laine S, Arvilommi H. Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain. Pediatr Res 1992; 32:141–144.

    PubMed  CAS  Google Scholar 

  89. Kaila M, Isolauri E, Saxelin M, Arvilommi H, Vesikari T. Viable versus inactivated lactoba-cillus strain GG in acute rotavirus diarrhoea. Arch Dis Child 1995; 72:51–53.

    Article  PubMed  CAS  Google Scholar 

  90. Isolauri E, Joensuu J, Suomalainen H, Luomala M, Vesikari T. Improved immunogenicity of oral D × RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine 1995; 13:310–312.

    Article  PubMed  CAS  Google Scholar 

  91. Malin M, Suomalainen H, Saxelin M, Isolauri E. Promotion of IgA immune response in patients with Crohn's disease by oral bacteriotherapy with Lactobacillus GG. Ann Nutr Metab 1996; 40:137–145.

    Article  PubMed  CAS  Google Scholar 

  92. Yasui H, Kiyoshima J, Ushijima H. Passive protection against rotavirus-induced diarrhea of mouse pups born to and nursed by dams fed Bifidobacterium breve YIT4064. J Infect Dis 1995; 172:403–409.

    PubMed  CAS  Google Scholar 

  93. Prokesová L, Ladmanová P, Cechova D, Stepánková R, Kozáková H, Mlcková Å, Kuklik R, Mára M. Stimulatory effects of Bacillus firmus on IgA production in human and mice. Immunol Lett 1999; 69:55–56.

    Google Scholar 

  94. Kalliomäki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001; 357:1076–1079.

    Article  PubMed  Google Scholar 

  95. Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003; 361:1869–1871.

    Article  PubMed  Google Scholar 

  96. Holloway JW, Koppelman GH. Identifying novel genes contributing to asthma pathogenesis. Curr Opin Allergy Clin Immunol. 2007; 7:69–74.

    Article  PubMed  CAS  Google Scholar 

  97. Rook GA, Stanford JL. Give us this day our daily germs. Immunol Today 1998; 19:113–116.

    Article  PubMed  CAS  Google Scholar 

  98. Erb KJ. Atopic disorders: a default pathway in the absence of infection? Immunol Today 1999; 20:317–322.

    Article  PubMed  CAS  Google Scholar 

  99. Kirjavainen P V, Gibson GR. Healthy gut microflora and allergy: factors influencing development of the microbiota. Ann Med 1999; 31:288–292.

    Article  PubMed  CAS  Google Scholar 

  100. Isolauri E, Grönlund MM, Salminen S, Arvilommi H. Why don't we bud? J Pediatr Gastroenterol Nutr 2000; 30:214–216.

    Article  PubMed  CAS  Google Scholar 

  101. Herz U, Lacy P, Renz H, Erb K. The influence of infections on the development and severity of allergic disorders. Curr Opin Immunol 2000; 12:632–640.

    Article  PubMed  CAS  Google Scholar 

  102. Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M, Bonini S. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. Br Med J 2000; 320:412–417.

    Article  CAS  Google Scholar 

  103. Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, Holt PG. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998; 160:4730–4737.

    PubMed  CAS  Google Scholar 

  104. Michaëlsson J, Mold JE, McCune JM, Nixon DF. Regulation of T cell responses in the developing human fetus. J Immunol 2006; 176:5741–5748.

    PubMed  Google Scholar 

  105. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531–562.

    Article  PubMed  CAS  Google Scholar 

  106. Cupedo T, Nagasawa M, Weijer K, Blom B, Spits H. Development and activation of regulatory T cells in the human fetus. Eur J Immunol 2005; 35:383–390.

    Article  PubMed  CAS  Google Scholar 

  107. Darrasse-Jèze G, Marodon G, Salomon BL, Catala M, Klatzmann D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 2005; 105:4715–4721.

    Article  PubMed  CAS  Google Scholar 

  108. Renz H, Blümer N, Virna S, Sel S, Garn H. The immunological basis of the hygiene hypothesis. In: The Environment (Ed.: Crameri R). Allergy and Asthma in Modern Society: A Scientific Approach. Chem Immunol Allergy. Karger, Basel 2006; 91:30–48.

    CAS  Google Scholar 

  109. Thornton CA, Upham JW, Wikstrom ME, Holt BJ, White GP, Sharp MJ, Sly PD, Holt PG. Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens. J Immunol 2004; 173:3084–3092.

    PubMed  CAS  Google Scholar 

  110. Rowe J, Kusel M, Holt BJ, Suriyaarachchi D, Serralha M, Hollams E, Yerkovich ST, Subrata LS, Ladyman C, Sadowska A, Gillett J, Fisher E, Loh R, Soderstrom L, Ahlstedt S, Sly PD, Holt PG. Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort. J Allergy Clin Immunol 2007; 119:1164–1173.

    Article  PubMed  CAS  Google Scholar 

  111. Holt PG, Thomas WR. Sensitization to airborne environmental allergens: unresolved issues. Nat Immunol 2005; 6:957–960.

    Article  PubMed  CAS  Google Scholar 

  112. van der Kleij D, Latz E, Brouwers JF, Kruize YC, Schmitz M, Kurt-Jones EA, Espevik T, de Jong EC, Kapsenberg ML, Golenbock DT, Tielens AG, Yazdanbakhsh M. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J Biol Chem 2002; 277:48122–48129.

    Article  PubMed  Google Scholar 

  113. Sepp E, Julge K, Vasar M, Naaber P, Björksten B, Mikelsaar M. Intestinal microflora of Estonian and Swedish infants. Acta Paediatr 1997; 86:956–961.

    Article  PubMed  CAS  Google Scholar 

  114. Björkstén B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999; 29:342–346.

    Article  PubMed  Google Scholar 

  115. Kalliomäki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001; 107:129–134.

    Article  PubMed  Google Scholar 

  116. Kaza U, Knight AK, Bahna SL. Risk factors for the development of food allergy. Curr Allergy Asthma Rep 2007; 7:182–186.

    Article  PubMed  Google Scholar 

  117. Collins MD, Gibson GR. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999; 69:1052S–1057S.

    PubMed  CAS  Google Scholar 

  118. Kalliomaki MA, Isolauri E. Probiotics and down-regulation of the allergic response. Immunol Allergy Clin North Am 2004; 24:739–752.

    Article  PubMed  Google Scholar 

  119. Zeiger RS. Dietary aspects of food allergy prevention in infants and children. J Pediatr Gastroenterol Nutr 2000; 30(Suppl):S77–86.

    Article  PubMed  Google Scholar 

  120. Hoppu U, Kalliomäki M, Laiho K, Isolauri E. Breast milk – immunomodulatory signals against allergic diseases. Allergy 2001; 56(Suppl 67):23–26.

    Article  PubMed  Google Scholar 

  121. Perez PF, Dore J, Leclerc M, Levenez F, Benyacoub J, Serrant P, Segura-Roggero I, Schiffrin EJ, Donnet-Hughes A. Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics 2007; 119:e724–732.

    Article  PubMed  Google Scholar 

  122. Miettinen M, Matikainen S, Vuopio-Varkila J, Pirhonen J, Varkila K, Kurimoto M, Julkunen I. Lactobacilli and streptococci induce interleukin-12 (IL-12), IL-18, and gamma interferon production in human peripheral blood mononuclear cells. Infect Immun 1998; 66:6058–6062.

    PubMed  CAS  Google Scholar 

  123. Hessle C, Hanson LA, Wold AE. Lactobacilli from human gastrointestinal mucosa are strong stimulators of IL-12 production. Clin Exp Immunol 1999; 116:276–282.

    Article  PubMed  CAS  Google Scholar 

  124. Hessle C, Andersson B, Wold AE. Gram-positive bacteria are potent inducers of monocytic interleukin-12 (IL-12) while gram-negative bacteria preferentially stimulate IL-10 production. Infect Immun 2000; 68:3581–3586.

    Article  PubMed  CAS  Google Scholar 

  125. Hessle C, Hanson LA, Wold AE. Interleukin-10 produced by the innate immune system masks in vitro evidence of acquired T-cell immunity to E. coli. Scand J Immunol 2000; 52:13–20.

    Article  PubMed  CAS  Google Scholar 

  126. Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000; 289:1352–1355.

    Article  PubMed  CAS  Google Scholar 

  127. Holt PG. Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? Lancet 2000; 356:1699–1701.

    Article  PubMed  CAS  Google Scholar 

  128. Mellor AL, Munn D. Policing pregnancy: Tregs help keep the peace. Trends Immunol 2004; 25:563–565.

    Article  PubMed  CAS  Google Scholar 

  129. Vassallo R, Tamada K, Lau JS, Kroening PR, Chen L. Cigarette smoke extract suppresses human dendritic cell function leading to preferential induction of Th-2 priming. J Immunol 2005; 175:2684–2691.

    PubMed  CAS  Google Scholar 

  130. Traidl-Hoffmann C, Mariani V, Hochrein H, Karg K, Wagner H, Ring J, Mueller MJ, Jakob T, Behrendt H. Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization. J Exp Med 2005; 201: 627–36. (Erratum in: J Exp Med 2005; 201:1347).

    Article  PubMed  CAS  Google Scholar 

  131. Trak-Fellermeier MA, Brasche S, Winkler G, Koletzko B, Heinrich J. Food and fatty acid intake and atopic disease in adults. Eur Respir J 2004; 23:575–582.

    Article  PubMed  CAS  Google Scholar 

  132. Devereux G, Seaton A. Diet as a risk factor for atopy and asthma. J Allergy Clin Immunol 2005; 115:1109–1117.

    Article  PubMed  Google Scholar 

  133. Dunstan JA, Prescott SL. Does fish oil supplementation in pregnancy reduce the risk of allergic disease in infants? Curr Opin Allergy Clin Immunol 2005; 5:215–221.

    PubMed  CAS  Google Scholar 

  134. Korotkova M, Telemo E, Yamashiro Y, Hanson LA, Strandvik B. The ratio of n-6 to n-3 fatty acids in maternal diet influences the induction of neonatal immunological tolerance to ovalbumin. Clin Exp Immunol 2004; 137:237–244.

    Article  PubMed  CAS  Google Scholar 

  135. Oddy WH, Pal S, Kusel MM, Vine D, de Klerk NH, Hartmann P, Holt PG, Sly PD, Burton PR, Stanley FJ, Landau LI. Atopy, eczema and breast milk fatty acids in a high-risk cohort of children followed from birth to 5 yr. Pediatr Allergy Immunol 2006; 17:4–10.

    Article  PubMed  Google Scholar 

  136. Wijga AH, van Houwelingen AC, Kerkhof M, Tabak C, de Jongste JC, Gerritsen J, Boshuizen H, Brunekreef B, Smit HA. Breast milk fatty acids and allergic disease in preschool children: the prevention and incidence of asthma and mite allergy birth cohort study. J Allergy Clin Immunol 2006; 117:440–447.

    Article  PubMed  CAS  Google Scholar 

  137. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 2005; 201:713–722.

    Article  PubMed  CAS  Google Scholar 

  138. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004; 21:527–538.

    Article  PubMed  CAS  Google Scholar 

  139. 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. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006; 314: 1157–1160.

    Article  PubMed  CAS  Google Scholar 

  140. Thorstenson KM, Khoruts A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 2001; 167:188–195.

    PubMed  CAS  Google Scholar 

  141. Zhang X, Izikson L, Liu L, Weiner HL. Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J Immunol 2001; 167:4245–4253.

    PubMed  CAS  Google Scholar 

  142. Karlsson MR, Kahu H, Hanson LA, Telemo E, Dahlgren UI. Tolerance and bystander suppression, with involvement of CD25-positive cells, is induced in rats receiving serum from ovalbumin-fed donors. Immunology 2000; 100:326–333.

    Article  PubMed  CAS  Google Scholar 

  143. Karlsson MR, Kahu H, Hanson LA, Telemo E, Dahlgren UI. An established immune response against ovalbumin is suppressed by a transferable serum factor produced after ovalbumin feeding: a role of CD25+ regulatory cells. Scand J Immunol 2002; 55:470–477.

    Article  PubMed  CAS  Google Scholar 

  144. Hauet-Broere F, Unger WW, Garssen J, Hoijer MA, Kraal G, Samsom JN. Functional CD25− and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application. Eur J Immunol 2003; 33:2801–2810.

    Article  PubMed  CAS  Google Scholar 

  145. Karlsson M, Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD+CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J Exp Med 2004; 199: 1679–1688.

    Article  PubMed  CAS  Google Scholar 

  146. Warner JO. The early life origins of asthma and related allergic disorders. Arch Dis Child 2004; 89:97–102.

    Article  PubMed  CAS  Google Scholar 

  147. Jones CA, Vance GH, Power LL, Pender SL, Macdonald TT, Warner JO. Costimulatory molecules in the developing human gastrointestinal tract: a pathway for fetal allergen priming. J Allergy Clin Immunol 2001; 108:235–241.

    Article  PubMed  CAS  Google Scholar 

  148. Haddeland U, Brandtzaeg P, Nakstad B. Maternal allergy influences the proliferation of neonatal T cells expressing CCR4, CXCR5 or CD103. Clin Exp Allergy 2007; 37:856–864.

    Article  PubMed  CAS  Google Scholar 

  149. Haddeland U, Karstensen AB, Farkas L, Bø KO, Pirhonen J, Karlsson M, Kvåvik W, Brandtzaeg P, Nakstad B. Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr Allergy Immunol 2005; 16:104–112.

    Article  PubMed  Google Scholar 

  150. Haddeland U, Sletten GB, Brandtzaeg P, Nakstad B. Impaired interleukin (IL)-4-associated generation of CCR4-expressing T cells in neonates with hereditary allergy risk. Clin Exp Immunol 2005; 139:314–322.

    Article  PubMed  CAS  Google Scholar 

  151. Locke NR, Stankovic S, Funda DP, Harrison LC. TCRγδ intraepithelial lymphocytes are required for self-tolerance. J Immunol 2006; 176: 6553–6559.

    PubMed  CAS  Google Scholar 

  152. Scott H, Nilsen E, Sollid LM, Lundin KEA, Rugtveit J, Molberg Ø, et al. Immunopathology of gluten-sensitive enteropathy. Springer Semin Immunopathol 1997; 18:535–553.

    Article  PubMed  CAS  Google Scholar 

  153. Halstensen TS, Brandtzaeg P. Activated T lymphocytes in the celiac lesion: non- proliferative activation (CD25) of CD4+ α/β cells in the lamina propria but proliferation (Ki-67) of α/β and γ/δ cells in the epithelium. Eur J Immunol 1993; 23:505–510.

    Article  PubMed  CAS  Google Scholar 

  154. Halstensen TS, Scott H, Fausa O, Brandtzaeg P. Gluten stimulation of coeliac mucosa in vitro induces activation (CD25) of lamina propria CD4+ T cells and macrophages but no crypt cell hyperplasia. Scand J Immunol 1993; 38:581–590.

    Article  PubMed  CAS  Google Scholar 

  155. Lundin KEA, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, et al. Gliadin-specific, HLA-DQ(α1*0501, β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med 1993; 178:187–196.

    Article  PubMed  CAS  Google Scholar 

  156. Molberg Ø, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KE. Gliadin-specific, HLA-DQ2 restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol 1997; 46:103–109.

    Article  CAS  Google Scholar 

  157. Scott H, Sollid LM, Fausa O, Brandtzaeg P, Thorsby E. Expression of major histocompatibility complex class II subregion products by jejunal epithelium in patients with coeliac disease. Scand J Immunol 1987; 26:563–571.

    Article  PubMed  CAS  Google Scholar 

  158. Sturgess RP, Macartney JC, Makgoba MW, Hung CH, Haskard DO, Ciclitira PJ. Differential upregulation of intercellular adhesion molecule-1 in coeliac disease. Clin Exp Immunol 1990; 82:489–492.

    Article  PubMed  CAS  Google Scholar 

  159. Rugtveit J, Sollid LM, Fausa O, Scott H, Brandtzaeg P. Upregulation of the CD40 and CD86 on HLA-DQ+ mucosal macrophages in coeliac disease. Abstract 36, Scand J Immunol 1997: 437.

    Google Scholar 

  160. Raki M, Tollefsen S, Molberg O, Lundin KE, Sollid LM, Jahnsen FL. A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells. Gastroenterology 2006;131:428–38. (Erratum in: Gastroenterology 2007; 132: 826–827).

    Article  PubMed  CAS  Google Scholar 

  161. Nilsen EM, Lundin KEA, Krajci P, Scott H, Sollid LM, Brandtzaeg P. Gluten-specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon γ. Gut 1995; 37:766–776.

    Article  PubMed  CAS  Google Scholar 

  162. Nilsen EM, Jahnsen FL, Lundin KEA, Johansen F-E, Fausa O, Sollid LM, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 1998; 115:551–563.

    Article  PubMed  CAS  Google Scholar 

  163. Brandtzaeg P, Halstensen TS, Huitfeldt HS, Krajci K, Kvale D, Scott H, et al. Epithelial expression of HLA, secretory component (poly-Ig receptor), and adhesion molecules in the human alimentary tract. Ann NY Acad Sci 1992; 664:157–179.

    Article  PubMed  CAS  Google Scholar 

  164. Deem RL, Shanahan F, Targan SR. Triggered human mucosal T cells release tumour necrosis factor-α and interferon-γ which kill human colonic epithelial cells. Clin Exp Immunol 1991; 83:79–84.

    PubMed  CAS  Google Scholar 

  165. Madara JL, Stafford J. Interferon-γ directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest 1989; 83:724–727.

    Article  PubMed  CAS  Google Scholar 

  166. Halstensen TS, Hvatum M, Scott H, Fausa O, Brandtzaeg P. Association of subepithelial deposition of activated complement and immunoglobulin G and M response to gluten in celiac disease. Gastroenterology 1992; 102:751–759.

    PubMed  CAS  Google Scholar 

  167. Smart CJ, Calabrese A, Oakes DJ, Howdle PD, Trejdosiewicz LK Expression of the LFA-1 β2 integrin (CD11a/CD18) and ICAM-1 (CD54) in normal and coeliac small bowel mucosa. Scand J Immunol 1991; 34:299–305.

    Article  PubMed  CAS  Google Scholar 

  168. Brandtzaeg P: Compartmentalized migration of mucosal B cells: normal dichotomy and disease-associated alterations. In: Cell Adhesion Molecules in Health and Disease (Eds.: Reutter W, Schuppan D, Tauber R, Zeitz M). Kluwer, London, 2003: 99–114.

    Google Scholar 

  169. Chowers Y, Marsh MN, De Grandpre L, Nyberg A, Theofilopoulos AN, Kagnoff MF. Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge. Clin Exp Immunol 1997; 107: 141–147.

    Article  PubMed  CAS  Google Scholar 

  170. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2:647–655.

    Article  PubMed  CAS  Google Scholar 

  171. Lundin KE, Sollid LM, Anthonsen D, Norén O, Molberg Ø, Thorsby E, et al. Heterogeneous reactivity patterns of HLA-D-Qrestricted, small intestinal T-cell clones from patients with celiac disease. Gastroenterology 1997; 112:752–759.

    Article  PubMed  CAS  Google Scholar 

  172. Arentz-Hansen H, McAdam SN, Molberg Ø, Fleckenstein B, Lundin KE, Jørgensen TJ, et al. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 2002; 123:803–809.

    Article  PubMed  CAS  Google Scholar 

  173. Qiao SW, Bergseng E, Molberg O, Xia J, Fleckenstein B, Khosla C, Sollid LM. Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. J Immunol 2004; 173:1757–1762.

    PubMed  CAS  Google Scholar 

  174. Boldogh I, Bacsi A, Choudhury BK, Dharajiya N, Alam R, Hazra TK, et al. ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest 2005; 115:2169–79.

    Article  PubMed  CAS  Google Scholar 

  175. Brandtzaeg P, Farstad IN, Helgeland L. Phenotypes of T cells in the gut. In: Mucosal T cells (Ed.: MacDonald TT), Karger, Basel. Chem Immunol 1998; 71:1–26.

    Google Scholar 

  176. Ebert EC. Intra-epithelial lymphocytes: interferon-gamma production and suppressor/cyto-toxic activities. Clin Exp Immunol 1990; 82:81–85.

    PubMed  CAS  Google Scholar 

  177. Hayday A, Theodoridis E, Ramsburg E, Shires J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat Immunol 2001; 2:997–1003.

    Article  PubMed  CAS  Google Scholar 

  178. Grdic D, Hörnquist E, Kjerrulf M, Lycke NY. Lack of local suppression in orally tolerant CD8-deficient mice reveals a critical regulatory role of CD8+ T cells in the normal gut mucosa. J Immunol 1998; 160:754–762.

    PubMed  CAS  Google Scholar 

  179. Mennechet FJ, Kasper LH, Rachinel N, Minns LA, Luangsay S, Vandewalle A, et al. Intestinal intraepithelial lymphocytes prevent pathogen-driven inflammation and regulate the Smad/T-bet pathway of lamina propria CD4+ T cells. Eur J Immunol 2004; 34:1059–1067.

    Article  PubMed  CAS  Google Scholar 

  180. Halstensen TS, Brandtzaeg P. Activated T lymphocytes in the celiac lesion: non- proliferative activation (CD25) of CD4+ α/β cells in the lamina propria but proliferation (Ki-67) of α/β and γ/δ cells in the epithelium. Eur J Immunol 1993; 23:505–510.

    Article  PubMed  CAS  Google Scholar 

  181. Selby WS, Painter D, Collins A, Faulkner-Hogg KB, Loblay RH. Persistent mucosal abnormalities in coeliac disease are not related to the ingestion of trace amounts of gluten. Scand J Gastroenterol 1999; 34:909–914.

    Article  PubMed  CAS  Google Scholar 

  182. Olaussen RW, Johansen FE, Lundin KE, Jahnsen J, Brandtzaeg P, Farstad IN. Interferon-γ-secreting T cells localize to the epithelium in coeliac disease. Scand J Immunol 2002; 56:652–664.

    Article  PubMed  CAS  Google Scholar 

  183. Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarström S, Hammarström ML. Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology 2002; 123:667–678.

    Article  PubMed  CAS  Google Scholar 

  184. Ishikawa H, Li Y, Abeliovich A, Yamamoto S, Kaufmann SH, Tonegawa S. Cytotoxic and interferon γ-producing activities of γδ T cells in the mouse intestinal epithelium are strain dependent. Proc Natl Acad Sci USA 1993; 90:8204–8208.

    Article  PubMed  CAS  Google Scholar 

  185. Gianfrani C, Troncone R, Mugione P, Cosentini E, De Pascale M, Faruolo C, et al. A. Celiac disease association with CD8+ T cell responses: identification of a novel gliadin-derived HLA-A2-restricted epitope. J Immunol 2003; 170:2719–2726.

    PubMed  CAS  Google Scholar 

  186. Ciccocioppo R, Di Sabatino A, Parroni R, Muzi P, D'Alo S, Ventura T, et al. Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease. Am J Clin Pathol 2001; 115:494–503.

    Article  PubMed  CAS  Google Scholar 

  187. Green PH, Jabri B. Coeliac disease. Lancet 2003; 362:383–391.

    Article  PubMed  CAS  Google Scholar 

  188. Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, et al. A direct role for NKG2D/ MICA interaction in villous atrophy during celiac disease. Immunity 2004; 21:367–377.

    Article  PubMed  Google Scholar 

  189. Jabri B, de Serre NP, Cellier C, Evans K, Gache C, Carvalho C, et al. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 2000; 118:867–879.

    Article  PubMed  CAS  Google Scholar 

  190. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004; 21:357–366.

    Article  PubMed  CAS  Google Scholar 

  191. Benahmed M, Meresse B, Arnulf B, Barbe U, Mention JJ, Verkarre V, Allez M, Cellier C, Hermine O, Cerf-Bensussan N. Inhibition of TGF-β signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease. Gastroenterology 2007; 132:994–1008.

    Article  PubMed  CAS  Google Scholar 

  192. Maiuri L, Ciacci C, Auricchio S, Brown V, Quaratino S, Londei M. Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology 2000;119:996–1006.

    Article  PubMed  CAS  Google Scholar 

  193. Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 2003;125:730–745.

    Article  PubMed  CAS  Google Scholar 

  194. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 2003; 362:30–37.

    Article  PubMed  CAS  Google Scholar 

  195. Maiuri L, Picarelli A, Boirivant M, Coletta S, Mazzilli MC, De Vincenzi M, et al. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology 1996; 110:1368–1378.

    Article  PubMed  CAS  Google Scholar 

  196. Tuckova L, Novotna J, Novak P, Flegelova Z, Kveton T, Jelinkova L, et al. Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol 2002; 71:625–631.

    PubMed  CAS  Google Scholar 

  197. Nikulina M, Habich C, Flohe SB, Scott FW, Kolb H. Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol 2004; 173:1925–1933.

    PubMed  CAS  Google Scholar 

  198. Palová-Jelínková L, Rozková D, Pecharová B, Bártová J, Sedivá A, Tlaskalova-Hogenová H, et al. Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol 2005; 175:7038–7045.

    PubMed  Google Scholar 

  199. Matysiak-Budnik T, Candalh C, Dugave C, Namane A, Cellier C, Cerf-Bensussan N, Heyman M. Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 2003; 125:696–707.

    Article  PubMed  CAS  Google Scholar 

  200. Matvsiak-Budnik T, Moura IC, Arcos-Faiardo M, Lebreton C, Ménard S, Candalh C, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008; 205(1):143–154.

    Article  CAS  Google Scholar 

  201. Cerf-Bensussan N, Matysiak-Budnik T, Cellier C, Heyman M. Oral proteases: a new approach to managing coeliac disease. Gut 2007; 56:157–160.

    Article  PubMed  CAS  Google Scholar 

  202. Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005; 2:416–422.

    Article  PubMed  CAS  Google Scholar 

  203. Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 2006; 41:408–419.

    Article  PubMed  CAS  Google Scholar 

  204. Olaussen RW, Karlsson MR, Lundin KE, Jahnsen J, Brandtzaeg P, Farstad IN. Reduced chemokine receptor 9 on intraepithelial lymphocytes in celiac disease suggests persistent epithelial activation. Gastroenterology. 2007; 132:2371–2382.

    Article  PubMed  CAS  Google Scholar 

  205. Olaussen RW, Løvik A, Tollefsen S, Andresen PA, Vatn MH, De Lange T, et al. Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease. Clin Gastroenterol Hepatol 2005; 3:875–885.

    Article  PubMed  CAS  Google Scholar 

  206. Frossard CP, Hauser C, Eigenmann PA. Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. J Allergy Clin Immunol 2004; 114:377–382.

    Article  PubMed  CAS  Google Scholar 

  207. Latcham F, Merino F, Lang A, Garvey J, Thomson MA, Walker-Smith JA, Davies SE, Phillips AD, Murch SH. A consistent pattern of minor immunodeficiency and subtle enter-opathy in children with multiple food allergy. J Pediatr 2003; 143:39–47.

    Article  PubMed  Google Scholar 

  208. Corthesy B. Roundtrip ticket for secretory IgA: role in mucosal homeostasis? J Immunol 2007; 178:27–32.

    PubMed  CAS  Google Scholar 

  209. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005; 122:107–118.

    Article  PubMed  CAS  Google Scholar 

  210. Wahn U. What drives the allergic march? Allergy 2000; 55:591–599.

    Article  PubMed  CAS  Google Scholar 

  211. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001; 1:69–75.

    Article  PubMed  CAS  Google Scholar 

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  1. Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute and Division of Pathology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway, N-0027

    Per Brandtzaeg

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  1. Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan

    Ruby Pawankar

  2. Southampton General Hospital, University of Southampton, Tremona Road, Southampton, UK

    Stephen T. Holgate

  3. Childrens's Mercy Hospital and Clinic, UMKC School of Medicine, 2401 Gillham Road, Kansas City, MO, 64108, USA

    Lanny J. Rosenwasser

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© 2009 Springer-Verlag Berlin Heidelberg

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Brandtzaeg, P. (2009). Mucosal Immunity: from Allergy to Coeliac Disease. In: Pawankar, R., Holgate, S.T., Rosenwasser, L.J. (eds) Allergy Frontiers: Classification and Pathomechanisms. Allergy Frontiers, vol 2. Springer, Tokyo. https://doi.org/10.1007/978-4-431-88315-9_31

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  • DOI: https://doi.org/10.1007/978-4-431-88315-9_31

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-88314-2

  • Online ISBN: 978-4-431-88315-9

  • eBook Packages: MedicineMedicine (R0)

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