Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Food allergy: separating the science from the mythology

Nature Reviews Gastroenterology & Hepatology volume 7, pages 380–400 (2010)Cite this article

Subjects

A Correction to this article was published on 01 September 2010

Abstract

Numerous genes are involved in innate and adaptive immunity and these have been modified over millions of years. During this evolution, the mucosal immune system has developed two anti-inflammatory strategies: immune exclusion by the use of secretory antibodies to control epithelial colonization of microorganisms and to inhibit the penetration of potentially harmful agents; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens, such as food proteins. The latter strategy is called oral tolerance when induced via the gut. Homeostatic mechanisms also dampen immune responses to commensal bacteria. The mucosal epithelial barrier and immunoregulatory network are poorly developed in newborns. The perinatal period is, therefore, critical with regard to the induction of food allergy. The development of immune homeostasis depends on windows of opportunity during which innate and adaptive immunity are coordinated by antigen-presenting cells. The function of these cells is not only orchestrated by microbial products but also by dietary constituents, including vitamin A and lipids, such as polyunsaturated omega-3 fatty acids. These factors may in various ways exert beneficial effects on the immunophenotype of the infant. The same is true for breast milk, which provides immune-inducing factors and secretory immunoglobulin A, which reinforces the gut epithelial barrier. It is not easy to dissect the immunoregulatory network and identify variables that lead to food allergy. This Review discusses efforts to this end and outlines the scientific basis for future food allergy prevention.

Key Points

  • Homeostasis in the gut mucosa is normally preserved by secretory IgA-dependent immune exclusion of antigens and by the suppression of proinflammatory responses to innocuous antigens by mucosally induced tolerance (oral tolerance)

  • Food allergy is considered to be the consequence of abrogation of oral tolerance due to inappropriate interactions between genes and the environment

  • Any event causing epithelial barrier defects may underlie food allergen sensitization, not only in the gut but also elsewhere in the body, such as the skin and airways

  • The successful induction of oral tolerance depends on the dose and timing of enteric exposure to potential allergens, immune-modulating microbial components and dietary factors, such as vitamin A and lipids

  • Strict allergen avoidance during pregnancy, lactation, and early childhood to prevent food allergy in families that are genetically at high risk of allergy seems to be based on mythology rather than science

  • Exclusive breastfeeding for 4 months and mixed feeding thereafter will probably promote tolerance to food allergens in newborns

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Classification of adverse reactions to foods according to pathogenic mechanisms.9
Figure 2: Anti-inflammatory mucosal adaptive immune defense mechanisms.
Figure 3: The intestinal immune system.
Figure 4: Depiction of an experimental mouse model of interactions between oral tolerance and immune hypersensitivity.
Figure 5: Maintenance of mucosal homeostasis in the gut and the abrogation of oral tolerance.
Figure 6: Putative integration of maternal SIgA into the immune system of a breastfed infant via M-cell-mediated Ag uptake.
Figure 7: Putative mechanisms of oral tolerance induction.
Figure 8: Conditioning of APCs for tolerance induction.
Figure 9: T-cell activation and differentiation.
Figure 10: Influence of the environment on gut–host communication and immunological development.
Figure 11: Biological variables that influence the developing immunophenotype of an infant.

Similar content being viewed by others

References

  1. Bischoff, S. & Crowe, S. E. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology 128, 1089–1113 (2005).

    CAS  PubMed  Google Scholar 

  2. Sicherer, S. H. & Sampson, H. A. Food allergy: recent advances in pathophysiology and treatment. Annu. Rev. Med. 60, 261–277 (2009).

    CAS  PubMed  Google Scholar 

  3. Cianferoni, A. & Spergel, J. M. Food allergy: review, classification and diagnosis. Allergol. Int. 58, 457–466 (2009).

    CAS  PubMed  Google Scholar 

  4. Eigenmann, P. A. et al. New visions for food allergy: an iPAC summary and future trends. Pediatr. Allergy Immunol. 19 (Suppl. 19), 26–39 (2008).

    PubMed  Google Scholar 

  5. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. Nat. Rev. Immunol. 6, 869–874 (2006).

    CAS  PubMed  Google Scholar 

  6. Rona, R. J. et al. The prevalence of food allergy: a meta-analysis. J. Allergy Clin. Immunol. 120, 638–646 (2007).

    PubMed  Google Scholar 

  7. Venter, C. et al. Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life. Allergy 63, 354–359 (2008).

    CAS  PubMed  Google Scholar 

  8. Lack, G. Epidemiologic risks for food allergy. J. Allergy Clin. Immunol. 121, 1331–1336 (2008).

    CAS  PubMed  Google Scholar 

  9. Bruijnzeel-Koomen, C. et al. Adverse reactions to food. European Academy of Allergology and Clinical Immunology Subcommittee. Allergy 50, 623–635 (1995).

    CAS  PubMed  Google Scholar 

  10. Johansson, S. G. et al. A revised nomenclature for allergy: an EAACI position statement from the EAACI nomenclature task force. Allergy 56, 813–824 (2001).

    CAS  PubMed  Google Scholar 

  11. Zopf, Y., Baenkler, H. W., Silbermann, A., Hahn E. G. & Raithel, M. The differential diagnosis of food intolerance. Dtsch Arztebl. Int. 106, 359–369 (2009).

    PubMed  PubMed Central  Google Scholar 

  12. Gell, P. G. H. & Coombs, R. R. A. (Eds) Clinical Aspects of Immunology 1st edn (Blackwell Science Ltd, Oxford, 1963).

    Google Scholar 

  13. Brandtzaeg, P. The changing immunological paradigm in coeliac disease. Immunol. Lett. 105, 127–139 (2006).

    CAS  PubMed  Google Scholar 

  14. Johansson, S. G. et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 113, 832–836 (2004).

    CAS  PubMed  Google Scholar 

  15. Plaut, M., Sawyer, R. T. & Fenton, M. J. Summary of the 2008 National Institute of Allergy and Infectious Diseases—US Food and Drug Administration workshop on food allergy clinical trial design. J. Allergy Clin. Immunol. 124, 671–678e1 (2009).

    PubMed  Google Scholar 

  16. Niggemann, B. et al. Controlled oral food challenges in children—when indicated, when superfluous? Allergy 60, 865–870 (2005).

    CAS  PubMed  Google Scholar 

  17. Allen, K. J. et al. Management of cow's milk protein allergy in infants and young children: an expert panel perspective. J. Paediatr. Child. Health 45, 481–486 (2009).

    PubMed  Google Scholar 

  18. Bischoff, S. C., Mayer, J. H. & Manns, M. P. Allergy and the gut. Int. Arch. Allergy Immunol. 121, 270–283 (2000).

    CAS  PubMed  Google Scholar 

  19. 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. 37, 27–34 (2003).

    CAS  PubMed  Google Scholar 

  20. 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 54, 346–351 (1999).

    CAS  PubMed  Google Scholar 

  21. Bischoff, S. C. Physiological and pathophysiological functions of intestinal mast cells. Semin. Immunopathol. 31, 185–205 (2009).

    CAS  PubMed  Google Scholar 

  22. Knutson, T. W. et al. Intestinal reactivity in allergic and nonallergic patients: an approach to determine the complexity of the mucosal reaction. J. Allergy Clin. Immunol. 91, 553–559 (1993).

    CAS  PubMed  Google Scholar 

  23. Bengtsson, U. et al. Increased levels of hyaluronan and albumin after intestinal challenge in adult patients with cow's milk intolerance. Clin. Exp. Allergy 26, 96–103 (1996).

    CAS  PubMed  Google Scholar 

  24. Bengtsson, U. et al. Eosinophil cationic protein and histamine after intestinal challenge in patients with cow's milk intolerance. J. Allergy Clin. Immunol. 100, 216–221 (1997).

    CAS  PubMed  Google Scholar 

  25. Lin, X. P. et al. Local allergic reaction in food-hypersensitive adults despite a lack of systemic food-specific IgE. J. Allergy Clin. Immunol. 109, 879–887 (2002).

    PubMed  Google Scholar 

  26. Brandtzaeg, P. Mechanisms of gastrointestinal reactions to food. Environ. Toxicol. Pharmacol. 4, 9–24 (1997).

    CAS  PubMed  Google Scholar 

  27. Groschwitz, K. R. et al. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proc. Natl Acad. Sci. USA 106, 22381–22386 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Maeda, N., Inomata, N., Morita, A., Kirino, M. & Ikezawa, Z. Correlation of oral allergy syndrome due to plant-derived foods with pollen sensitization in Japan. Ann. Allergy Asthma Immunol. 104, 205–210 (2010).

    CAS  PubMed  Google Scholar 

  29. Silva, R. et al. Anaphylaxis to mango fruit and crossreactivity with Artemisia vulgaris pollen. J. Investig. Allergol. Clin. Immunol. 19, 420–422 (2009).

    CAS  PubMed  Google Scholar 

  30. Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

    CAS  PubMed  Google Scholar 

  31. Brandtzaeg, P. “ABC” of mucosal immunology. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 23–43 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  32. Brandtzaeg, P. Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 70, 505–515 (2009).

    CAS  PubMed  Google Scholar 

  33. Guarner, F. et al. Mechanisms of disease: the hygiene hypothesis revisited. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 275–284 (2006).

    CAS  PubMed  Google Scholar 

  34. Björksten, B. The hygiene hypothesis: do we still believe in it? In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 11–22 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  35. Vickery, B. P. & Burks, A. W. Immunotherapy in the treatment of food allergy: focus on oral tolerance. Curr. Opin. Allergy Clin. Immunol. 9, 364–370 (2009).

    CAS  PubMed  Google Scholar 

  36. Scurlock, A. M., Burks, A. W. & Jones, S. M. Oral immunotherapy for food allergy. Curr. Allergy Asthma Rep. 9, 186–193 (2009).

    PubMed  Google Scholar 

  37. von Hertzen, L. C. et al. Scientific rationale for the Finnish Allergy Programme 2008–2018: emphasis on prevention and endorsing tolerance. Allergy 64, 678–701 (2009).

    CAS  PubMed  Google Scholar 

  38. Brandtzaeg, P. History of oral tolerance and mucosal immunity. Ann. NY Acad. Sci. 778, 1–27 (1996).

    CAS  PubMed  Google Scholar 

  39. Duchmann, R., Neurath, M., Märker-Hermann, E. & Meyer Zum Büschenfelde, K. H. Immune responses towards intestinal bacteria—current concepts and future perspectives. Z. Gastroenterol. 35, 337–346 (1997).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  41. Konrad, A., Cong, Y., Duck, W., Borlaza, R. & Elson, C. O. Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130, 2050–2059 (2006).

    CAS  PubMed  Google Scholar 

  42. Macpherson, A. J., Geuking, M. B. & McCoy, K. D. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 115, 153–162 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Neish, A. S. Microbes in gastrointestinal health and disease. Gastroenterology 136, 65–80 (2009).

    PubMed  Google Scholar 

  44. Duerkop, B. A., Vaishnava, S. & Hooper, L. V. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 31, 368–376 (2009).

    CAS  PubMed  Google Scholar 

  45. Brandtzaeg, P., Nilssen, D. E., Rognum, T. O. & Thrane, P. S. Ontogeny of the mucosal immune system and IgA deficiency. Gastroenterol. Clin. North Am. 20, 397–439 (1991).

    CAS  PubMed  Google Scholar 

  46. Holt, P. G. & Jones, C. A. The development of the immune system during pregnancy and early life. Allergy 55, 688–697 (2000).

    CAS  PubMed  Google Scholar 

  47. Brandtzaeg, P. Development and basic mechanisms of human gut immunity. Nutr. Rev. 56, S5–S18 (1998).

    CAS  PubMed  Google Scholar 

  48. Yamanaka, T. et al. Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer's patches. J. Immunol. 170, 816–822 (2003).

    CAS  PubMed  Google Scholar 

  49. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Brandtzaeg, P. & Johansen, F. E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol. Rev. 206, 32–63 (2005).

    CAS  PubMed  Google Scholar 

  51. Brandtzaeg, P. Function of mucosa-associated lymphoid tissue in antibody formation. Immunol. Invest. 39, 303–355 (2010).

    CAS  PubMed  Google Scholar 

  52. Neutra, M. R., Mantis, N. J. & Kraehenbuhl, J. P. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2, 1004–1009 (2001).

    CAS  PubMed  Google Scholar 

  53. Brandtzaeg, P. & Pabst, R. Let's go mucosal: communication on slippery ground. Trends Immunol. 25, 570–577 (2004).

    CAS  PubMed  Google Scholar 

  54. Kraus, T. A. et al. Induction of mucosal tolerance in Peyer's patch-deficient, ligated small bowel loops. J. Clin. Invest. 115, 2234–2243 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Worbs, T. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Brandtzaeg, P. Role of local immunity and breast-feeding in mucosal homeostasis and defence against infections. In Nutrition and Immune Function 1st edn Vol. 1 Ch. 14 (eds Calder, P. C., Field, C. J. & Gill, H. S.) 273–320 (CABI Publishing, Oxon, UK, 2002).

    Google Scholar 

  57. Brandtzaeg, P. The mucosal immune system and its integration with the mammary glands. J. Pediatr. 156 (Suppl. 2), S8–S15 (2010).

    CAS  PubMed  Google Scholar 

  58. Nahmias, A. et al. IgA-secreting cells in the blood of premature and term infants: normal development and effect of intrauterine infections. Adv. Exp. Med. Biol. 310, 59–69 (1991).

    CAS  PubMed  Google Scholar 

  59. Stoll, B. J. et al. Immunoglobulin secretion by the normal and the infected newborn infant. J. Pediatr. 122, 780–786 (1993).

    CAS  PubMed  Google Scholar 

  60. Siegrist, C. A. & Aspinall, R. B-cell responses to vaccination at the extremes of age. Nat. Rev. Immunol. 9, 185–194 (2009).

    CAS  PubMed  Google Scholar 

  61. Crabbé, P. A., Nash, D. R., Bazin, H., Eyssen, H. & Heremans, J. F. Immunohistochemical observations on lymphoid tissues from conventional and germ-free mice. Lab. Invest. 22, 448–457 (1970).

    PubMed  Google Scholar 

  62. Lodinová, R., Jouja, V. & Wagner, V. Serum immunoglobulins and coproantibody formation in infants after artificial intestinal colonization with Escherichia coli 083 and oral lysozyme administration. Pediatr. Res. 7, 659–669 (1973).

    PubMed  Google Scholar 

  63. Moreau, M. C., Ducluzeau, R., Guy-Grand, D. & Muller, M. C. Increase in the population of duodenal immunoglobulin A plasmocytes in axenic mice associated with different living or dead bacterial strains of intestinal origin. Infect. Immun. 21, 532–539 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).

    CAS  PubMed  Google Scholar 

  65. Upham, J. W. et al. Dendritic cell immaturity during infancy restricts the capacity to express vaccine-specific T-cell memory. Infect. Immun. 74, 1106–1112 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Marzi, M. et al. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin. Exp. Immunol. 106, 127–133 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Brandtzaeg, P. & Prydz, H. Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulins. Nature 311, 71–73 (1984).

    CAS  PubMed  Google Scholar 

  68. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bollinger, R. R. et al. Secretory IgA and mucin-mediated biofilm formation by environmental strains of Escherichia coli: role of type 1 pili. Mol. Immunol. 43, 378–387 (2006).

    CAS  PubMed  Google Scholar 

  70. Mellander, L., Carlsson, B., Jalil, F., Söderström, T. & Hanson, L. A. Secretory IgA antibody response against Escherichia coli antigens in infants in relation to exposure. J. Pediatr. 107, 430–433 (1985).

    CAS  PubMed  Google Scholar 

  71. Martino, D. J., Currie, H., Taylor, A., Conway, P. & Prescott, S. L. Relationship between early intestinal colonization, mucosal immunoglobulin A production and systemic immune development. Clin. Exp. Allergy 38, 69–78 (2008).

    CAS  PubMed  Google Scholar 

  72. Kukkonen, K. et al. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases. Pediatr. Allergy Immunol. 21, 67–73 (2010).

    PubMed  Google Scholar 

  73. Ogra, S. S., Weintraub, D. & Ogra, P. L. 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. 119, 245–248 (1977).

    CAS  PubMed  Google Scholar 

  74. Klemola, T., Savilahti, E. & Leinikki, P. Mumps IgA antibodies are not absorbed from human milk. Acta Paediatr. Scand. 75, 230–232 (1986).

    CAS  PubMed  Google Scholar 

  75. Weaver, L. T., Wadd, N., Taylor, C. E., Greenwell, J. & Toms, G. L. The ontogeny of serum IgA in the newborn. Pediatr. Allergy Immunol. 2, 2–75 (1991).

    Google Scholar 

  76. van Elburg, R. M., Uil, J. J., de Monchy, J. G. & Heymans, H. S. Intestinal permeability in pediatric gastroenterology. Scand. J. Gastroenterol. 194 (Suppl.), 19–24 (1992).

    CAS  Google Scholar 

  77. Johansen, F. E. et al. Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice. J. Exp. Med. 190, 915–921 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Sait, L. C. et al. Secretory antibodies reduce systemic antibody responses against the gastrointestinal commensal flora. Int. Immunol. 19, 257–265 (2007).

    CAS  PubMed  Google Scholar 

  79. Karlsson, M. R., Johansen, F. E., Kahu, H., Macpherson, A. & Brandtzaeg, P. Hypersensitivity and oral tolerance in the absence of a secretory immune system. Allergy 65, 561–570 (2010).

    CAS  PubMed  Google Scholar 

  80. Smith, M. et al. Children with egg allergy have evidence of reduced neonatal CD4+CD25+CD127lo/- regulatory T cell function. J. Allergy Clin. Immunol. 121, 1460–1466, 1466.e1–e7 (2008).

    CAS  PubMed  Google Scholar 

  81. Martino, D. J. & Prescott, S. L. Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease. Allergy 65, 1–15 (2009).

    Google Scholar 

  82. Haddeland, U. et al. Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr. Allergy Immunol. 16, 104–112 (2005).

    PubMed  Google Scholar 

  83. Janzi, M. et al. Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin. Immunol. 133, 78–85 (2009).

    CAS  PubMed  Google Scholar 

  84. Brandtzaeg, P. Impact of immunodeficiency on immunological homeostasis in the gut. In Falk Symposium 135—Immunological Diseases of Liver and Gut (eds Lukáš, M., Manns, M. P., Špicák, J. & Stange, E. F.) 180–209 (Kluwer Academic Publishers, Dordrecht, 2004).

    Google Scholar 

  85. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

    CAS  PubMed  Google Scholar 

  86. Neish, A. S. et al. Prokaryotic regulation of epithelial responses by inhibition of IκBα ubiquitination. Science 289, 1560–1563 (2000).

    CAS  PubMed  Google Scholar 

  87. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8, 411–420 (2008).

    CAS  PubMed  Google Scholar 

  88. Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat. Cell Biol. 8, 1327–1336 (2006).

    CAS  PubMed  Google Scholar 

  89. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    CAS  PubMed  Google Scholar 

  90. Rescigno, M., Lopatin, U. & Chieppa, M. Interactions among dendritic cells, macrophages, and epithelial cells in the gut: implications for immune tolerance. Curr. Opin. Immunol. 20, 669–675 (2008).

    CAS  PubMed  Google Scholar 

  91. Shale, M. & Ghosh, S. How intestinal epithelial cells tolerise dendritic cells and its relevance to inflammatory bowel disease. Gut 58, 1291–1299 (2009).

    CAS  PubMed  Google Scholar 

  92. Iliev, I. D. et al. Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 58, 1481–1489 (2009).

    CAS  PubMed  Google Scholar 

  93. Groschwitz, K. R. & Hogan, S. P. Intestinal barrier function: molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol. 124, 3–20 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Abreu, M. T., Palladino, A. A., Arnold, E. T., Kwon, R. S. & McRoberts, J. A. Modulation of barrier function during Fas-mediated apoptosis in human intestinal epithelial cells. Gastroenterology 119, 1524–1536 (2000).

    CAS  PubMed  Google Scholar 

  95. Lotz, M. et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973–984 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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. 112, 420–426 (2003).

    PubMed  Google Scholar 

  97. Latcham, F. et al. A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J. Pediatr. 143, 39–47 (2003).

    PubMed  Google Scholar 

  98. van Odijk, J. et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 58, 833–843 (2003).

    CAS  PubMed  Google Scholar 

  99. Ip, S. et al. Breastfeeding and Maternal and Infant Health Outcomes in Developed Countries. Agency for Healthcare Research and Quality [online], (2007).

    Google Scholar 

  100. Høst, A. et al. Dietary prevention of allergic diseases in infants and small children. Pediatr. Allergy Immunol. 19, 1–4 (2008).

    PubMed  Google Scholar 

  101. Prescott, S. L. et al. The importance of early complementary feeding in the development of oral tolerance: concerns and controversies. Pediatr. Allergy Immunol. 19, 375–380 (2008).

    PubMed  Google Scholar 

  102. Nwaru, B. I. et al. Age at the introduction of solid foods during the first year and allergic sensitization at age 5 years. Pediatrics 125, 50–59 (2010).

    PubMed  Google Scholar 

  103. Hanson, L. A. Session 1: feeding and infant development breast-feeding and immune function. Proc. Nutr. Soc. 66, 384–396 (2007).

    CAS  PubMed  Google Scholar 

  104. Corthésy, B. Roundtrip ticket for secretory IgA: role in mucosal homeostasis? J. Immunol. 178, 27–32 (2007).

    PubMed  Google Scholar 

  105. Savilahti E. et al. Low colostral IgA associated with cow's milk allergy. Acta Paediatr. Scand. 80, 1207–1213 (1991).

    CAS  PubMed  Google Scholar 

  106. Järvinen, K. M., Laine, S. T., Järvenpää, A. L. & Suomalainen, H. K. Does low IgA in human milk predispose the infant to development of cow's milk allergy? Pediatr. Res. 48, 457–462 (2000).

    PubMed  Google Scholar 

  107. Field, C. J. The immunological components of human milk and their effect on immune development in infants. J. Nutr. 135, 1–4 (2005).

    CAS  PubMed  Google Scholar 

  108. Planchon, S. M., Martins, C. A., Guerrant, R. L. & Roche, J. K. Regulation of intestinal epithelial barrier function by TGF-β1. Evidence for its role in abrogating the effect of a T cell cytokine. J. Immunol. 153, 5730–5739 (1994).

    CAS  PubMed  Google Scholar 

  109. Benn, C. S. et al. Breastfeeding and risk of atopic dermatitis, by parental history of allergy, during the first 18 months of life. Am. J. Epidemiol. 160, 217–223 (2004).

    PubMed  Google Scholar 

  110. Verhasselt, V. et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat. Med. 14, 170–175 (2008).

    CAS  PubMed  Google Scholar 

  111. Matson, A. P., Thrall, R. S., Rafti, E. & Puddington, L. Breastmilk from allergic mothers can protect offspring from allergic airway inflammation. Breastfeed Med. 4, 167–174 (2009).

    PubMed  PubMed Central  Google Scholar 

  112. López-Expósito, I., Song, Y., Järvinen, K. M., Srivastava, K. & Li, X. M. Maternal peanut exposure during pregnancy and lactation reduces peanut allergy risk in offspring. J. Allergy Clin. Immunol. 124, 1039–1046 (2009).

    PubMed  PubMed Central  Google Scholar 

  113. Simons, F. E. & Sampson, H. A. Anaphylaxis epidemic: fact or fiction? J. Allergy Clin. Immunol. 122, 1166–1168 (2008).

    PubMed  Google Scholar 

  114. Saurer, L. & Mueller, C. T cell-mediated immunoregulation in the gastrointestinal tract. Allergy 64, 505–519 (2009).

    CAS  PubMed  Google Scholar 

  115. Westendorf, A. M. et al. CD4+Foxp3+ regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells. Gut 58, 211–219 (2009).

    CAS  PubMed  Google Scholar 

  116. Broere, F. et al. Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4. Mucosal Immunol. 2, 254–264 (2009).

    CAS  PubMed  Google Scholar 

  117. Rothberg, R. M. & Farr, R. S. Anti-bovine serum albumine and anti-alpha lactalbumin in the serum of children and adults. Pediatrics 35, 571–588 (1965).

    CAS  PubMed  Google Scholar 

  118. Scott, H., Rognum, T. O., Midtvedt, T. & Brandtzaeg, P. Age-related changes of human serum antibodies to dietary and colonic bacterial antigens measured by an enzyme-linked immunosorbent assay. Acta Pathol. Microbiol. Immunol. Scand. C 93, 65–70 (1985).

    CAS  PubMed  Google Scholar 

  119. Korenblat, P. E., Rothberg, R. M., Minden, P. & Farr, R. S. Immune responses of human adults after oral and parenteral exposure to bovine serum albumin. J. Allergy 41, 226–235 (1968).

    CAS  PubMed  Google Scholar 

  120. Waldo, F. B., van den Wall Bake, A. W., Mestecky, J. & Husby, S. Suppression of the immune response by nasal immunization. Clin. Immunol. Immunopathol. 72, 30–34 (1994).

    CAS  PubMed  Google Scholar 

  121. Husby, S., Mestecky, J., Moldoveanu, Z., Holland, S. & Elson, C. O. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding. J. Immunol. 152, 4663–4670 (1994).

    CAS  PubMed  Google Scholar 

  122. Kraus, T. A., Toy, L., Chan, L., Childs, J. & Mayer, L. Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease. Gastroenterology 126, 1771–1778 (2004).

    CAS  PubMed  Google Scholar 

  123. Kraus, T. A., Cheifetz, A., Toy, L., Meddings, J. B. & Mayer, L. Evidence for a genetic defect in oral tolerance induction in inflammatory bowel disease. Inflamm. Bowel Dis. 12, 82–88 (2006).

    PubMed  Google Scholar 

  124. Qiao, L. et al. Differential regulation of human T cell responsiveness by mucosal versus blood monocytes. Eur. J. Immunol. 26, 922–927 (1996).

    CAS  PubMed  Google Scholar 

  125. Smith, P. D. et al. Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J. Immunol. 167, 2651–2656 (2001).

    CAS  PubMed  Google Scholar 

  126. Rugtveit, J. et al. Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology 112, 1493–1505 (1997).

    CAS  PubMed  Google Scholar 

  127. Weber, B., Saurer, L. & Mueller, C. Intestinal macrophages: differentiation and involvement in intestinal immunopathologies. Semin. Immunopathol. 31, 171–184 (2009).

    CAS  PubMed  Google Scholar 

  128. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8, 1086–1094 (2007).

    CAS  PubMed  Google Scholar 

  129. Rescigno, M. Before they were gut dendritic cells. Immunity 31, 454–456 (2009).

    CAS  PubMed  Google Scholar 

  130. Milling, S. W., Cousins, L. & MacPherson, G. G. How do DCs interact with intestinal antigens? Trends Immunol. 26, 349–352 (2005).

    CAS  PubMed  Google Scholar 

  131. Mowat, A. M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

    CAS  PubMed  Google Scholar 

  132. Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Grindebacke, H. et al. Dynamic development of homing receptor expression and memory cell differentiation of infant CD4+CD25high regulatory T cells. J. Immunol. 183, 4360–4370 (2009).

    CAS  PubMed  Google Scholar 

  134. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Hammerschmidt, S. I. et al. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J. Exp. Med. 205, 2483–2490 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Sakaguchi, S., Wing, K. & Yamaguchi, T. Dynamics of peripheral tolerance and immune regulation mediated by Treg. Eur. J. Immunol. 39, 2331–2336 (2009).

    CAS  PubMed  Google Scholar 

  137. Belkaid, Y. & Oldenhove, G. Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29, 362–371 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).

    CAS  PubMed  Google Scholar 

  139. Horwitz, D. A., Zheng, S. G. & Gray, J. D. Natural and TGF-β-induced Foxp3+CD4+ CD25+ regulatory T cells are not mirror images of each other. Trends Immunol. 29, 429–435 (2008).

    CAS  PubMed  Google Scholar 

  140. Akbar, A. N., Vukmanovic-Stejic, M., Taams, L. S. & Macallan, D. C. The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nat. Rev. Immunol. 7, 231–237 (2007).

    CAS  PubMed  Google Scholar 

  141. Schnoeller, C. et al. A helminth immunomodulator reduces allergic and inflammatory responses by induction of IL-10-producing macrophages. J. Immunol. 180, 4265–4272 (2008).

    CAS  PubMed  Google Scholar 

  142. Honda, K. & Takeda, K. Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol. 2, 187–196 (2009).

    CAS  PubMed  Google Scholar 

  143. Weinstock, J. V. & Elliott, D. E. Helminths and the IBD hygiene hypothesis. Inflamm. Bowel Dis. 15, 128–133 (2009).

    PubMed  Google Scholar 

  144. 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 35, 397–402 (2005).

    PubMed  Google Scholar 

  145. Gerhold, K. et al. Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J. Allergy Clin. Immunol. 118, 666–673 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  147. Hong, X., Tsai, H. J. & Wang, X. Genetics of food allergy. Curr. Opin. Pediatr. 21, 770–776 (2009).

    PubMed  PubMed Central  Google Scholar 

  148. Rook, G. A. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology 126, 3–11 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Fallon, P. G. & Mangan, N. E. Suppression of TH2-type allergic reactions by helminth infection. Nat. Rev. Immunol. 7, 220–230 (2007).

    CAS  PubMed  Google Scholar 

  150. Tang, M. L. Probiotics and prebiotics: immunological and clinical effects in allergic disease. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 219–238 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  151. Salminen, S., Collado, M. C., Isolauri, E. & Gueimonde, M. Microbial-host interactions: selecting the right probiotics and prebiotics for infants. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 201–217 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  152. Ghadimi, D., Vrese, M., Heller, K. J. & Schrezenmeir, J. Effect of natural commensal-origin DNA on toll-like receptor 9 (TLR9) signaling cascade, chemokine IL-8 expression, and barrier integritiy of polarized intestinal epithelial cells. Inflamm. Bowel Dis. 16, 410–427 (2010).

    PubMed  Google Scholar 

  153. Broide, D. H. Immunomodulation of allergic disease. Annu. Rev. Med. 60, 279–291 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Rancé, F., Boguniewicz, M. & Lau, S. New visions for atopic eczema: an iPAC summary and future trends. Pediatr. Allergy Immunol. 19 (Suppl. 19), 17–25 (2008).

    PubMed  Google Scholar 

  155. Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat. Rev. Immunol. 8, 169–182 (2008).

    CAS  PubMed  Google Scholar 

  156. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  158. Isolauri, E., Grönlund, M. M., Salminen, S. & Arvilommi, H. Why don't we bud? J. Pediatr. Gastroenterol. Nutr. 30, 214–216 (2000).

    CAS  PubMed  Google Scholar 

  159. Prescott, S. L. et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the TH2 cytokine profile. J. Immunol. 160, 4730–4737 (1998).

    CAS  PubMed  Google Scholar 

  160. Michaëlsson, J., Mold, J. E., McCune, J. M. & Nixon, D. F. Regulation of T cell responses in the developing human fetus. J. Immunol. 176, 5741–5748 (2006).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  162. Darrasse-Jèze, G., Marodon, G., Salomon, B. L., Catala, M. & Klatzmann, D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 105, 4715–4721 (2005).

    PubMed  Google Scholar 

  163. Renz, H., Pfefferle, P. I., Teich, R. & Garn, H. Development and regulation of immune responses to food antigens in pre- and postnatal life. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 139–157 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  164. Huehn, J., Polansky, J. K. & Hamann, A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat. Rev. Immunol. 9, 83–89 (2009).

    CAS  PubMed  Google Scholar 

  165. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).

    CAS  PubMed  Google Scholar 

  166. Conrad, M. L. et al. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J. Exp. Med. 206, 2869–2877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Takahashi, K., Sugi, Y., Hosono, A. & Kaminogawa, S. Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J. Immunol. 183, 6522–6529 (2009).

    CAS  PubMed  Google Scholar 

  168. Alford, S. H. et al. Parental history of atopic disease: disease pattern and risk of pediatric atopy in offspring. J. Allergy Clin. Immunol. 114, 1046–1050 (2004).

    PubMed  Google Scholar 

  169. Renz, H., Blümer, N., Virna, S., Sel, S. & Garn, H. in Allergy and Asthma in Modern Society: A Scientific Approach Vol. 91 (ed. Crameri, R.) 30–48 (Chem. Immunol. Allergy, Karger, Basel, 2006).

    Google Scholar 

  170. van der Kleij, D. et al. A novel host–parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277, 48122–48129 (2002).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  172. Rowe, J. et al. Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort. J. Allergy Clin. Immunol. 119, 1164–1173 (2007).

    CAS  PubMed  Google Scholar 

  173. Holt, P. G. & Thomas, W. R. Sensitization to airborne environmental allergens: unresolved issues. Nat. Immunol. 6, 957–960 (2005).

    CAS  PubMed  Google Scholar 

  174. Skripak, J. M., Matsui, E. C., Mudd, K. & Wood, R. A. The natural history of IgE-mediated cow's milk allergy. J. Allergy Clin. Immunol. 120, 1172–1177 (2007).

    CAS  PubMed  Google Scholar 

  175. Bird, J. A. & Burks, A. W. Food allergy and asthma. Prim. Care Respir. J. 18, 258–265 (2009).

    PubMed  PubMed Central  Google Scholar 

  176. Sepp, E. et al. Intestinal microflora of Estonian and Swedish infants. Acta Paediatr. 86, 956–961 (1997).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  178. Kalliomäki, M. et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J. Allergy Clin. Immunol. 107, 129–134 (2001).

    PubMed  Google Scholar 

  179. Eggesbø, M. et al. Cesarean delivery and cow milk allergy/intolerance. Allergy 60, 1172–1173 (2005).

    PubMed  Google Scholar 

  180. Koplin, J. et al. Is caesarean delivery associated with sensitization to food allergens and IgE-mediated food allergy: a systematic review. Pediatr. Allergy Immunol. 19, 682–687 (2008).

    PubMed  Google Scholar 

  181. Kuitunen, M. et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J. Allergy Clin. Immunol. 123, 335–341 (2009).

    PubMed  Google Scholar 

  182. Zeiger, R. S. Dietary aspects of food allergy prevention in infants and children. J. Pediatr. Gastroenterol. Nutr. 30 (Suppl.), S77–S86 (2000).

    PubMed  Google Scholar 

  183. Prescott, S. L. Role of dietary immunomodulatory factors in the development of immune tolerance. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.). 185–200 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  184. Perez, P. F. et al. Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics 119, e724–e732 (2007).

    PubMed  Google Scholar 

  185. Miettinen, M. et al. Lactobacilli and streptococci induce interleukin-12 (IL-12), IL-18, and gamma interferon production in human peripheral blood mononuclear cells. Infect. Immun. 66, 6058–6062 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Hessle, C., Hanson, L. A. & Wold, A. E. Lactobacilli from human gastrointestinal mucosa are strong stimulators of IL-12 production. Clin. Exp. Immunol. 116, 276–282 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Hessle, C., Hanson, L. A. & Wold, A. E. Interleukin-10 produced by the innate immune system masks in vitro evidence of acquired T-cell immunity to E. coli. Scand. J. Immunol. 52, 13–20 (2000).

    CAS  PubMed  Google Scholar 

  189. Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).

    CAS  PubMed  Google Scholar 

  190. Caramalho, I. et al. Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 197, 403–411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178–1184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Li, B. et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int. Immunol. 19, 825–835 (2007).

    CAS  PubMed  Google Scholar 

  193. Holt, P. G. Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? Lancet 356, 1699–1701 (2000).

    CAS  PubMed  Google Scholar 

  194. Mellor, A. L. & Munn, D. Policing pregnancy: Tregs help keep the peace. Trends Immunol. 25, 563–565 (2004).

    CAS  PubMed  Google Scholar 

  195. Vassallo, R., Tamada, K., Lau, J. S., Kroening, P. R. & Chen, L. Cigarette smoke extract suppresses human dendritic cell function leading to preferential induction of Th-2 priming. J. Immunol. 175, 2684–2691 (2005).

    CAS  PubMed  Google Scholar 

  196. Traidl-Hoffmann, C. et al. Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization. J. Exp. Med. 201, 627–636 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Lin, J. & Sampson, H. A. The role of immunoglobulin E-binding epitopes in the characterization of food allergy. Curr. Opin. Allergy Clin. Immunol. 9, 357–363 (2009).

    CAS  PubMed  Google Scholar 

  198. O'Gorman, W. E. et al. The initial phase of an immune response functions to activate regulatory T cells. J. Immunol. 183, 332–339 (2009).

    CAS  PubMed  Google Scholar 

  199. Du Toit, G. et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J. Allergy Clin. Immunol. 122, 984–991 (2008).

    CAS  PubMed  Google Scholar 

  200. Fox, A. T., Sasieni, P., du Toit, G., Syed, H. & Lack, G. Household peanut consumption as a risk factor for the development of peanut allergy. J. Allergy Clin. Immunol. 123, 417–423 (2009).

    CAS  PubMed  Google Scholar 

  201. Wennergren, G. What if it is the other way around? Early introduction of peanut and fish seems to be better than avoidance. Acta Paediatr. 98, 1085–1087 (2009).

    PubMed  Google Scholar 

  202. Greer, F. R., Sicherer, S. H. & Burks, A. W. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 121, 183–191 (2008).

    PubMed  Google Scholar 

  203. Sicherer, S. H. & Burks, A. W. Maternal and infant diets for prevention of allergic diseases: understanding menu changes in 2008. J. Allergy Clin. Immunol. 122, 29–33 (2008).

    PubMed  Google Scholar 

  204. Mazer, B. Specific oral tolerance induction increased tolerance to milk in children with severe cow's milk allergy. Evid. Based Med. 14, 50 (2009).

    PubMed  Google Scholar 

  205. Staden, U. et al. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 62, 1261–1269 (2007).

    CAS  PubMed  Google Scholar 

  206. Skripak, J. M. et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J. Allergy Clin. Immunol. 122, 1154–1160 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Rancé, F. Novel approaches in treating food allergy using allergens. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 157–167 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  208. Nowak-Wegrzyn, A. et al. Tolerance to extensively heated milk in children with cow's milk allergy. J. Allergy Clin. Immunol. 122, 342–347.e2 (2008).

    PubMed  Google Scholar 

  209. Bannon, G. A. et al. Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int. Arch. Allergy Immunol. 124, 70–72 (2001).

    CAS  PubMed  Google Scholar 

  210. Calder, P. C. et al. Early nutrition and immunity—progress and perspectives. Br. J. Nutr. 96, 774–790 (2006).

    CAS  PubMed  Google Scholar 

  211. Sampson, H. A. Role of complementary and alternative medicine in the field of allergy and clinical immunology. J. Allergy Clin. Immunol. 123, 317–318 (2009).

    PubMed  Google Scholar 

  212. Srivastava, K. D. et al. Food Allergy Herbal Formula-2 silences peanut-induced anaphylaxis for a prolonged posttreatment period via IFN-gamma-producing CD8+ T cells. J. Allergy Clin. Immunol. 123, 443–451 (2009).

    CAS  PubMed  Google Scholar 

  213. Furuhjelm, C. et al. Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr. 98, 1461–1467 (2009).

    PubMed  Google Scholar 

  214. Sandin, A., Bråbäck, L., Norin, E. & Björkstén, B. Faecal short chain fatty acid pattern and allergy in early childhood. Acta Paediatr. 98, 823–827 (2009).

    PubMed  Google Scholar 

  215. Korotkova, M., Telemo, E., Yamashiro, Y., Hanson, L. A. & 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. 137, 237–244 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Oddy, W. H. et al. Atopy, eczema and breast milk fatty acids in a high-risk cohort of children followed from birth to 5 yr. Pediatr. Allergy Immunol. 17, 4–10 (2006).

    PubMed  Google Scholar 

  217. Wijga, A. H. et al. 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. 117, 440–447 (2006).

    CAS  PubMed  Google Scholar 

  218. Arita, M. et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    CAS  PubMed  Google Scholar 

  220. Maloy, K. J. et al. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    CAS  PubMed  Google Scholar 

  223. Sutmuller, R. P. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Hrncir, T., Stepankova, R., Kozakova, H., Hudcovic, T. & Tlaskalova-Hogenova, H. Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice. BMC Immunol. 9, 65 (2008).

    PubMed  PubMed Central  Google Scholar 

  225. Corthay, A. How do regulatory T cells work? Scand. J. Immunol. 70, 326–336 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    CAS  PubMed  Google Scholar 

  227. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    CAS  PubMed  Google Scholar 

  228. Thorstenson, K. M. & 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. 167, 188–195 (2001).

    CAS  PubMed  Google Scholar 

  229. Zhang, X., Izikson, L., Liu, L. & Weiner, H. L. Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J. Immunol. 167, 4245–4253 (2001).

    CAS  PubMed  Google Scholar 

  230. Karlsson, M. R., Kahu, H., Hanson, L. A., Telemo, E. & Dahlgren, U. I. Tolerance and bystander suppression, with involvement of CD25-positive cells, is induced in rats receiving serum from ovalbumin-fed donors. Immunology 100, 326–333 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Karlsson, M. R., Kahu, H., Hanson, L. A., Telemo, E. & Dahlgren, U. I. 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. 55, 470–477 (2002).

    CAS  PubMed  Google Scholar 

  232. Curotto de Lafaille, M. A. et al. Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29, 114–126 (2008).

    CAS  PubMed  Google Scholar 

  233. Boirivant, M. et al. A transient breach in the epithelial barrier leads to regulatory T-cell generation and resistance to experimental colitis. Gastroenterology 135, 1612–1623.e5 (2008).

    CAS  PubMed  Google Scholar 

  234. Karlsson, M. R., Rugtveit, J. & Brandtzaeg, P. Allergen-responsive CD+CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J. Exp. Med. 199, 1679–1688 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Sletten, G. B., Halvorsen, R., Egaas, E. & Halstensen, T. S. Memory T cell proliferation in cow's milk allergy after CD25+ regulatory T cell removal suggests a role for casein-specific cellular immunity in IgE-mediated but not in non-IgE-mediated cow's milk allergy. Int. Arch. Allergy Immunol. 142, 190–198 (2007).

    CAS  PubMed  Google Scholar 

  236. Shreffler, W. G., Wanich, N., Moloney, M., Nowak-Wegrzyn, A. & Sampson, H. A. Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein. J. Allergy Clin. Immunol. 123, 43–52.e7 (2009).

    CAS  PubMed  Google Scholar 

  237. Tiemessen, M. M. et al. Cow's milk-specific T-cell reactivity of children with and without persistent cow's milk allergy: key role for IL-10. J. Allergy Clin. Immunol. 113, 932–939 (2004).

    CAS  PubMed  Google Scholar 

  238. Frossard, C. P., Hauser, C. & Eigenmann, P. A. Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. J. Allergy Clin. Immunol. 114, 377–382 (2004).

    CAS  PubMed  Google Scholar 

  239. Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon. J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell. Host Microbe 2, 328–339 (2007).

    CAS  PubMed  Google Scholar 

  240. Atherton, J. C. & Blaser, M. J. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J. Clin. Invest. 119, 2475–2487 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Untersmayr, E. & Jensen-Jarolim, E. The role of protein digestibility and antacids on food allergy outcomes. J. Allergy Clin. Immunol. 121, 1301–1308 (2008).

    PubMed  PubMed Central  Google Scholar 

  242. Mullins, R. J. Paediatric food allergy trends in a community-based specialist allergy practice, 1995–2006. Med. J. Aust. 186, 618–621 (2007).

    PubMed  Google Scholar 

  243. Rickard, C. Response to “Health risks of genetically modified foods”. Crit. Rev. Food Sci. Nutr. 50, 85–91 (2010).

    PubMed  Google Scholar 

  244. Guimarães, V. D. et al. Comparative study of the adjuvanticity of Bacillus thuringiensis Cry1Ab protein and cholera toxin on allergic sensitisation and elicitation to peanut. Food Agric. Immunol. 19, 325–337 (2008).

    Google Scholar 

  245. Prescott, V. E. et al. Transgenic expression of bean α-amylase inhibitor in peas results in altered structure and immunogenicity. J. Agric. Food Chem. 53, 9023–9030 (2005).

    CAS  PubMed  Google Scholar 

  246. Finamore, A. et al. Intestinal and peripheral immune response to MON810 maize ingestion in weaning and old mice. J. Agric. Food Chem. 56, 11533–11539 (2008).

    CAS  PubMed  Google Scholar 

  247. Brandtzaeg, P. & Tolo, K. Mucosal penetrability enhanced by serum-derived antibodies. Nature 266, 262–263 (1977).

    CAS  PubMed  Google Scholar 

  248. Lim, P. L. & Rowley, D. The effect of antibody on the intestinal absorption of macromolecules and on intestinal permeability in adult mice. Int. Arch. Allergy Appl. Immunol. 68, 41–46 (1982).

    CAS  PubMed  Google Scholar 

  249. Werfel, T. The role of leukocytes, keratinocytes, and allergen-specific IgE in the development of atopic dermatitis. J. Invest. Dermatol. 129, 1878–1891 (2009).

    CAS  PubMed  Google Scholar 

  250. Arima, K. et al. Distinct signal codes generate dendritic cell functional plasticity. Sci. Signal. 3, ra4 (2010).

    PubMed  PubMed Central  Google Scholar 

  251. Michelson, P. H., Williams, L. W., Benjamin, D. K. & Barnato, A. E. Obesity, inflammation, and asthma severity in childhood: data from the National Health and Nutrition Examination Survey 2001–2004. Ann. Allergy Asthma Immunol. 103, 381–385 (2009).

    PubMed  Google Scholar 

  252. Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

    CAS  PubMed  Google Scholar 

  253. von Berg, A. Modified proteins in allergy prevention. In Microbial–Host Interaction: Tolerance versus Allergy Vol. 64 (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 239–250 (Nestec Ltd, Vevey & Karger, A. G., Basel, Switzerland, 2009).

    Google Scholar 

  254. Sopo, S. M., Onesimo, R., Giorgio, V. & Fundarò, C. Specific oral tolerance induction (SOTI) in pediatric age: Clinical research or just routine practice? Pediatr. Allergy Immunol. 21, e446–e449 (2010).

    PubMed  Google Scholar 

  255. Jones, S. M. et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J. Allergy Clin. Immunol. 124, 292–300.e97 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Goubier, A. et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29, 464–475 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Bamboat, Z. M. et al. Human liver dendritic cells promote T cell hyporesponsiveness. J. Immunol. 182, 1901–1911 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is grateful to H. Eliassen for excellent secretarial assistance. Studies discussed here conducted at LIIPAT were supported by the Research Council of Norway, the Norwegian Cancer Society, the University of Oslo, and Oslo University Hospital.

Author information

Authors and Affiliations

  1. University of Oslo and Department and Institute of Pathology, Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), Oslo University Hospital, Rikshospitalet, Oslo, N-0027, Norway

    Per Brandtzaeg

Authors
  1. Per Brandtzaeg
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brandtzaeg, P. Food allergy: separating the science from the mythology. Nat Rev Gastroenterol Hepatol 7, 380–400 (2010). https://doi.org/10.1038/nrgastro.2010.80

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2010.80

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing