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Mucosal immunology of tolerance and allergy in the gastrointestinal tract

  • Immunology at Mount Sinai
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Abstract

The mucosal immune system typically exists in a state of active tolerance to food antigens and commensal bacteria. Tolerance to food proteins is induced in part by dendritic cells residing in the intestinal mucosa and implemented by regulatory T cells. Food allergy occurs when immune tolerance is disrupted and a sensitizing immune response characterized by food-specific IgE production occurs instead. Experimental food allergy in mice requires use of adjuvant or exploitation of alternate routes of sensitization to induce allergic sensitization, and can aid in understanding the mechanisms of sensitization to food allergens and the pathophysiology of gastrointestinal manifestations of food allergy. Recent work in the understanding of mucosal immunology of tolerance and allergy in the gastrointestinal tract will be discussed.

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References

  1. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549–55.

    Article  PubMed  Google Scholar 

  2. Wells HG. Studies on the chemistry of anaphylaxis [III]. Experiments with isolated proteins, especially those of the hen’s egg. J Infect Dis. 1911;9(2):147–71.

    Article  CAS  Google Scholar 

  3. Wells HG, Osborne TB. The biological reactions of the vegetable proteins. J Infect Dis. 1911;8(1):66–124.

    Article  CAS  Google Scholar 

  4. Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol. 2005;115(1):3–12.

    Article  PubMed  Google Scholar 

  5. Mayer L. Mucosal immunity. Immunol Rev. 2005;206:5.

    Article  PubMed  Google Scholar 

  6. Perrier C, Corthesy B. Gut permeability and food allergies. Clin Exp Allergy. 2011;41(1):20–8.

    Article  PubMed  CAS  Google Scholar 

  7. Michael JG. The role of digestive enzymes in orally induced immune tolerance. Immunol Invest. 1989;18(9–10):1049–54.

    Article  PubMed  CAS  Google Scholar 

  8. Menard S, Cerf-Bensussan N, Heyman M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 2010;3(3):247–59.

    Article  PubMed  CAS  Google Scholar 

  9. Chen Y, Inobe J, Weiner HL. Induction of oral tolerance to myelin basic protein in CD8-depleted mice: Both CD4+ and CD8+ cells mediate active suppression. J Immunol. 1995;155(2):910–6.

    PubMed  CAS  Google Scholar 

  10. Zhang X, Izikson L, Liu L, Weiner HL. Activation of CD25[+]CD4[+] regulatory T cells by oral antigen administration. J Immunol. 2001;167(8):4245–53.

    PubMed  CAS  Google Scholar 

  11. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994;265(5176):1237–40.

    Article  PubMed  CAS  Google Scholar 

  12. Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest. 1996;98(1):70–7.

    Article  PubMed  CAS  Google Scholar 

  13. Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011;34(2):237–46.

    Article  PubMed  CAS  Google Scholar 

  14. Cassani B, Villablanca EJ, Quintana FJ, Love PE, Lacy-Hulbert A, Blaner WS, et al. Gut-tropic T cells that express integrin alpha4beta7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology. 2011;141(6):2109–18.

    Article  PubMed  CAS  Google Scholar 

  15. Arnaboldi PM, Roth-Walter F, Mayer L. Suppression of Th1 and Th17, but not Th2, responses in a CD8[+] T cell-mediated model of oral tolerance. Mucosal Immunol. 2009;2(5):427–38.

    Article  PubMed  CAS  Google Scholar 

  16. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204(8):1757–64.

    Article  PubMed  CAS  Google Scholar 

  17. Worbs T, Bode U, Yan S, Hoffmann MW, Hintzen G, Bernhardt G, et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med. 2006;203(3):519–27.

    Article  PubMed  CAS  Google Scholar 

  18. Dubois B, Joubert G, Gomez de Aguero M, Gouanvic M, Goubier A, Kaiserlian D. Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance. Gastroenterology. 2009;137(3):1019–28.

    Article  PubMed  CAS  Google Scholar 

  19. Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity. 2008;29(3):464–75.

    Article  PubMed  CAS  Google Scholar 

  20. 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(7):1771–8.

    Article  PubMed  CAS  Google Scholar 

  21. Turcanu V, Maleki SJ, Lack G. Characterization of lymphocyte responses to peanuts in normal children, peanut-allergic children, and allergic children who acquired tolerance to peanuts. J Clin Invest. 2003;111(7):1065–72.

    PubMed  CAS  Google Scholar 

  22. Prussin C, Yin Y, Upadhyaya B. T[H]2 heterogeneity: does function follow form? J Allergy Clin Immunol. 2010;126(6):1094–8.

    Article  PubMed  CAS  Google Scholar 

  23. DeLong JH, Simpson KH, Wambre E, James EA, Robinson D, Kwok WW. Ara h 1-reactive T cells in individuals with peanut allergy. J Allergy Clin Immunol. 2011;127(5):1211–8. e3.

    Article  PubMed  CAS  Google Scholar 

  24. Flinterman AE, Pasmans SG, den Hartog Jager CF, Hoekstra MO, Bruijnzeel-Koomen CA, Knol EF, et al. T cell responses to major peanut allergens in children with and without peanut allergy. Clin Exp Allergy. 2010;40(4):590–7.

    PubMed  CAS  Google Scholar 

  25. Adel-Patient K, Bernard H, Ah-Leung S, Creminon C, Wal JM. Peanut- and cow’s milk-specific IgE, Th2 cells and local anaphylactic reaction are induced in Balb/c mice orally sensitized with cholera toxin. Allergy. 2005;60(5):658–64.

    Article  PubMed  CAS  Google Scholar 

  26. Snider DP, Marshall JS, Perdue MH, Liang H. Production of IgE antibody and allergic sensitization of intestinal and peripheral tissues after oral immunization with protein ag and cholera toxin. J Immunol. 1994;153(2):647–57.

    PubMed  CAS  Google Scholar 

  27. Li XM, Schofield BH, Huang CK, Kleiner GI, Sampson HA. A murine model of IgE-mediated cow’s milk hypersensitivity. J Allergy Clin Immunol. 1999;103(2 Pt 1):206–14.

    Article  PubMed  CAS  Google Scholar 

  28. Li XM, Serebrisky D, Lee SY, Huang CK, Bardina L, Schofield BH, et al. A murine model of peanut anaphylaxis: T- and B-cell responses to a major peanut allergen mimic human responses. J Allergy Clin Immunol. 2000;106(1 Pt 1):150–8.

    Article  PubMed  CAS  Google Scholar 

  29. Blazquez AB, Berin MC. Gastrointestinal dendritic cells promote Th2 skewing via OX40L. J Immunol. 2008;180(7):4441–50.

    PubMed  CAS  Google Scholar 

  30. Yang PC, Xing Z, Berin CM, Soderholm JD, Feng BS, Wu L, et al. TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy. Gastroenterology. 2007;133(5):1522–33.

    Article  PubMed  CAS  Google Scholar 

  31. Feng BS, Chen X, He SH, Zheng PY, Foster J, Xing Z, et al. Disruption of T-cell immunoglobulin and mucin domain molecule [TIM]-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model. J Allergy Clin Immunol. 2008;122(1):55–61. e1–7.

    Article  PubMed  CAS  Google Scholar 

  32. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. 2003;112(6):1203–7.

    Article  PubMed  Google Scholar 

  33. Lack G, Fox D, Northstone K, Golding J, Avon Longitudinal Study of Parents and Children Study Team. Factors associated with the development of peanut allergy in childhood. N Engl J Med. 2003;348(11):977–85.

    Article  PubMed  Google Scholar 

  34. Birmingham NP, Parvataneni S, Hassan HM, Harkema J, Samineni S, Navuluri L, et al. An adjuvant-free mouse model of tree nut allergy using hazelnut as a model tree nut. Int Arch Allergy Immunol. 2007;144(3):203–10.

    Article  PubMed  CAS  Google Scholar 

  35. Gonipeta B, Parvataneni S, Tempelman RJ, Gangur V. An adjuvant-free mouse model to evaluate the allergenicity of milk whey protein. J Dairy Sci. 2009;92(10):4738–44.

    Article  PubMed  CAS  Google Scholar 

  36. Hsieh KY, Tsai CC, Wu CH, Lin RH. Epicutaneous exposure to protein antigen and food allergy. Clin Exp Allergy. 2003;33(8):1067–75.

    Article  PubMed  Google Scholar 

  37. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest. 1998;101(8):1614–22.

    Article  PubMed  CAS  Google Scholar 

  38. He R, Oyoshi MK, Wang JY, Hodge MR, Jin H, Geha RS. The prostaglandin D receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge. J Allergy Clin Immunol. 2010;126(4):784–90.

    Article  PubMed  CAS  Google Scholar 

  39. Dioszeghy V, Mondoulet L, Dhelft V, Ligouis M, Puteaux E, Benhamou PH, et al. Epicutaneous immunotherapy results in rapid allergen uptake by dendritic cells through intact skin and downregulates the allergen-specific response in sensitized mice. J Immunol. 2011;186(10):5629–37.

    Article  PubMed  CAS  Google Scholar 

  40. C D, Berin MC, Mayer L. Allergic sensitization can be induced via multiple physiologic routes in an adjuvant-dependent manner. J Allergy Clin Immunol. 2011;128(6):1251–8. e2.

    Google Scholar 

  41. Lehrer SB, Ayuso R, Reese G. Current understanding of food allergens. Ann N Y Acad Sci. 2002;964:69–85.

    Article  PubMed  CAS  Google Scholar 

  42. Peyron S, Mouecoucou J, Fremont S, Sanchez C, Gontard N. Effects of heat treatment and pectin addition on beta-lactoglobulin allergenicity. J Agric Food Chem. 2006;54(15):5643–50.

    Article  PubMed  CAS  Google Scholar 

  43. Thomas K, Herouet-Guicheney C, Ladics G, Bannon G, Cockburn A, Crevel R, et al. Evaluating the effect of food processing on the potential human allergenicity of novel proteins: International workshop report. Food Chem Toxicol. 2007;45(7):1116–22.

    Article  PubMed  CAS  Google Scholar 

  44. Bernhisel-Broadbent J, Strause D, Sampson HA. Fish hypersensitivity. II: Clinical relevance of altered fish allergenicity caused by various preparation methods. J Allergy Clin Immunol. 1992;90(4 Pt 1):622–9.

    Article  PubMed  CAS  Google Scholar 

  45. Roth-Walter F, Berin MC, Arnaboldi P, Escalante CR, Dahan S, Rauch J, et al. Pasteurization of milk proteins promotes allergic sensitization by enhancing uptake through Peyer’s patches. Allergy. 2008;63(7):882–90.

    Article  PubMed  CAS  Google Scholar 

  46. Martos G, Lopez-Exposito I, Bencharitiwong R, Berin MC, Nowak-Wegrzyn A. Mechanisms underlying differential food allergy response to heated egg. J Allergy Clin Immunol. 2011;127(4):990–7. e2.

    Article  PubMed  CAS  Google Scholar 

  47. Lemon-Mule H, Sampson HA, Sicherer SH, Shreffler WG, Noone S, Nowak-Wegrzyn A. Immunologic changes in children with egg allergy ingesting extensively heated egg. J Allergy Clin Immunol. 2008;122(5):977–83. e1.

    Article  PubMed  CAS  Google Scholar 

  48. Des Roches A, Nguyen M, Paradis L, Primeau MN, Singer S. Tolerance to cooked egg in an egg allergic population. Allergy. 2006;61(7):900–1.

    Article  PubMed  CAS  Google Scholar 

  49. Nowak-Wegrzyn A, Bloom KA, Sicherer SH, Shreffler WG, Noone S, Wanich N, et al. Tolerance to extensively heated milk in children with cow’s milk allergy. J Allergy Clin Immunol. 2008;122(2):342-7. e2.

    Article  PubMed  Google Scholar 

  50. Kim JS, Nowak-Wegrzyn A, Sicherer SH, Noone S, Moshier EL, Sampson HA. Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol. 2011;128(1):125–31. e2.

    Article  PubMed  CAS  Google Scholar 

  51. Strait RT, Mahler A, Hogan S, Khodoun M, Shibuya A, Finkelman FD. Ingested allergens must be absorbed systemically to induce systemic anaphylaxis. J Allergy Clin Immunol. 2011;127(4):982–9. e1.

    Article  PubMed  CAS  Google Scholar 

  52. Berin MC, Kiliaan AJ, Yang PC, Groot JA, Taminiau JA, Perdue MH. Rapid transepithelial antigen transport in rat jejunum: impact of sensitization and the hypersensitivity reaction. Gastroenterology. 1997;113(3):856–64.

    Article  PubMed  CAS  Google Scholar 

  53. Berin MC, Kiliaan AJ, Yang PC, Groot JA, Kitamura Y, Perdue MH. The influence of mast cells on pathways of transepithelial antigen transport in rat intestine. J Immunol. 1998;161(5):2561–6.

    PubMed  CAS  Google Scholar 

  54. Yang PC, Berin MC, Yu LC, Conrad DH, Perdue MH. Enhanced intestinal transepithelial antigen transport in allergic rats is mediated by IgE and CD23 [FcepsilonRII]. J Clin Invest. 2000;106(7):879–86.

    Article  PubMed  CAS  Google Scholar 

  55. Li H, Nowak-Wegrzyn A, Charlop-Powers Z, Shreffler W, Chehade M, Thomas S, et al. Transcytosis of IgE-antigen complexes by CD23a in human intestinal epithelial cells and its role in food allergy. Gastroenterology. 2006;131(1):47–58.

    Article  PubMed  CAS  Google Scholar 

  56. Tu Y, Perdue MH. CD23-mediated transport of IgE/immune complexes across human intestinal epithelium: Role of p38 MAPK. Am J Physiol Gastrointest Liver Physiol. 2006;291(3):G532–8.

    Article  PubMed  CAS  Google Scholar 

  57. Finkelman FD. Anaphylaxis: lessons from mouse models. J Allergy Clin Immunol. 2007;120(3):506–15. quiz 516–7.

    Article  PubMed  CAS  Google Scholar 

  58. Strait RT, Morris SC, Yang M, Qu XW, Finkelman FD. Pathways of anaphylaxis in the mouse. J Allergy Clin Immunol. 2002;109(4):658–68.

    Article  PubMed  CAS  Google Scholar 

  59. Sun J, Arias K, Alvarez D, Fattouh R, Walker T, Goncharova S, et al. Impact of CD40 ligand, B cells, and mast cells in peanut-induced anaphylactic responses. J Immunol. 2007;179(10):6696–703.

    PubMed  CAS  Google Scholar 

  60. Arias K, Chu DK, Flader K, Botelho F, Walker T, Arias N, et al. Distinct immune effector pathways contribute to the full expression of peanut-induced anaphylactic reactions in mice. J Allergy Clin Immunol. 2011;127(6):1552–61. e1.

    Article  PubMed  CAS  Google Scholar 

  61. Arias K, Baig M, Colangelo M, Chu D, Walker T, Goncharova S, et al. Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions. J Allergy Clin Immunol. 2009;124(2):307–14. e2.

    Article  PubMed  CAS  Google Scholar 

  62. Lin XP, Magnusson J, Ahlstedt S, Dahlman-Hoglund A, Hanson LLA, Magnusson O, et al. Local allergic reaction in food-hypersensitive adults despite a lack of systemic food-specific IgE. J Allergy Clin Immunol. 2002;109(5):879–87.

    Article  PubMed  Google Scholar 

  63. Brandt EB, Strait RT, Hershko D, Wang Q, Muntel EE, Scribner TA, et al. Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest. 2003;112(11):1666–77.

    PubMed  CAS  Google Scholar 

  64. Knight AK, Blazquez AB, Zhang S, Mayer L, Sampson HA, Berin MC. CD4 T cells activated in the mesenteric lymph node mediate gastrointestinal food allergy in mice. Am J Physiol Gastrointest Liver Physiol. 2007;293(6):G1234–43.

    Article  PubMed  CAS  Google Scholar 

  65. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–56.

    Article  PubMed  CAS  Google Scholar 

  66. Wu D, Ahrens R, Osterfeld H, Noah TK, Groschwitz K, Foster PS, et al. Interleukin-13 [IL-13]/IL-13 receptor alpha1 [IL-13Ralpha1] signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent cl- secretion. J Biol Chem. 2011;286(15):13357–69.

    Article  PubMed  CAS  Google Scholar 

  67. Brandt EB, Munitz A, Orekov T, Mingler MK, McBride M, Finkelman FD, et al. Targeting IL-4/IL-13 signaling to alleviate oral allergen-induced diarrhea. J Allergy Clin Immunol. 2009;123(1):53–8.

    Article  PubMed  CAS  Google Scholar 

  68. Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008;205(4):897–913.

    Article  PubMed  CAS  Google Scholar 

  69. Osterfeld H, Ahrens R, Strait R, Finkelman FD, Renauld JC, Hogan SP. Differential roles for the IL-9/IL-9 receptor alpha-chain pathway in systemic and oral antigen-induced anaphylaxis. J Allergy Clin Immunol. 2010;125(2):469–76. e2.

    Article  PubMed  CAS  Google Scholar 

  70. Groschwitz KR, Hogan SP. Intestinal barrier function: Molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009;124(1):3–20.

    Article  PubMed  CAS  Google Scholar 

  71. Li H, Chehade M, Liu W, Xiong H, Mayer L, Berin MC. Allergen-IgE complexes trigger CD23-dependent CCL20 release from human intestinal epithelial cells. Gastroenterology. 2007;133(6):1905–15.

    Article  PubMed  CAS  Google Scholar 

  72. Blazquez AB, Knight AK, Getachew H, Bromberg JS, Lira SA, Mayer L, et al. A functional role for CCR6 on proallergic T cells in the gastrointestinal tract. Gastroenterology. 2010;138(1):275–84. e4.

    Article  PubMed  CAS  Google Scholar 

  73. Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol. 2010;11(4):289–93.

    Article  PubMed  CAS  Google Scholar 

  74. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673–80.

    PubMed  CAS  Google Scholar 

  75. Liu YJ. Thymic stromal lymphopoietin: Master switch for allergic inflammation. J Exp Med. 2006;203(2):269–73.

    Article  PubMed  Google Scholar 

  76. Taylor BC, Zaph C, Troy AE, Du Y, Guild KJ, Comeau MR, et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med. 2009;206(3):655–67.

    Article  PubMed  CAS  Google Scholar 

  77. Iliev ID, Mileti E, Matteoli G, Chieppa M, Rescigno M. Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2009;2(4):340–50.

    Article  PubMed  CAS  Google Scholar 

  78. Blazquez AB, Mayer L, Berin MC. Thymic stromal lymphopoietin is required for gastrointestinal allergy but not oral tolerance. Gastroenterology. 2010;139(4):1301–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Lauren Steele is supported by the Doris Duke Clinical Research Fellowship program. The work described from the Berin and Mayer labs was funded in part by NIH grant AI044236.

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Authors and Affiliations

  1. Mount Sinai School of Medicine, Immunology Institute, New York, NY, USA

    Lauren Steele, Lloyd Mayer & M. Cecilia Berin

  2. Pediatric Allergy and Immunology, Mount Sinai School of Medicine, Box 1198, One Gustave L. Levy Place, New York, NY, 10029, USA

    M. Cecilia Berin

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  1. Lauren Steele
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Correspondence to M. Cecilia Berin.

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Steele, L., Mayer, L. & Cecilia Berin, M. Mucosal immunology of tolerance and allergy in the gastrointestinal tract. Immunol Res 54, 75–82 (2012). https://doi.org/10.1007/s12026-012-8308-4

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