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.

Early life factors that affect allergy development

Nature Reviews Immunology volume 17, pages 518–528 (2017)Cite this article

Subjects

Key Points

  • The recent rise in the incidence of allergic disease suggests that changing environmental factors can influence the risk of allergic sensitization. Environmental exposures that occur during the first few months of life can influence the risk of allergy development in later childhood.

  • The timing of the first exposure to potential allergens, as well as the route of the first exposure, can influence whether tolerance or allergic sensitization occurs. Cutaneous antigen exposure predisposes towards a T helper 2 (TH2) cell-skewing environment, which leads to allergic sensitization, whereas oral antigen exposure predisposes towards tolerogenic responses that are mediated by retinal dehydrogenase 2 (RALDH2)-expressing CD103+ dendritic cells.

  • Exposure to microbial endotoxins alongside potential allergens can protect against allergic sensitization through the stimulation of innate pattern recognition receptors.

  • Many of the environmental factors that are associated with allergy development modify the composition and diversity of the microbiota. Recent studies have demonstrated that the microbiota composition in the first few months of life can be predictive of allergy development in later childhood, and studies in mice have demonstrated that the absence of key bacterial microbiota species can be a driving factor in allergy development.

  • Infection with pathogens can protect against allergic sensitization by promoting tolerogenic responses or can exacerbate existing disease by promoting the release of TH2 cell-skewing cytokines. Fungal infections and certain bacterial and viral species are associated with the exacerbation of existing allergies, whereas helminth species and certain bacterial and viral species are associated with protection against allergic sensitization.

  • It is clear that there are notable differences in the quality of immune responses to foreign antigens and stimuli even in the few weeks after birth in mice; how this developmental time window translates into the setting of human neonates is not yet clear. Both microorganism-derived and helminth-derived molecules have great potential for therapeutic and prophylactic use in infants who are at a high risk of developing allergies.

Abstract

The incidence of allergic disease continues to rise in industrialized countries. The rapid increase in the incidence of allergic disease throughout the past half century suggests that recently altered environmental factors are driving allergy development. Accumulating evidence suggests that environmental experiences that occur during the first months of life can influence the risk of allergic sensitization. In this Review, we present the evidence relating to specific early life exposures that affect future allergy development, and discuss how these exposures may promote either tolerance or allergic sensitization.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: The route of antigen exposure influences immune priming.
Figure 2: A diverse microbiota can inhibit allergic sensitization.
Figure 3: Developmental time windows in early life affect adult allergic sensitization in mice.

References

  1. Anagnostou, K., Meyer, R., Fox, A. & Shah, N. The rapidly changing world of food allergy in children. F1000Prime Rep. 7, 35 (2015).

    PubMed  PubMed Central  Google Scholar 

  2. Burks, A. W. et al. ICON: food allergy. J. Allergy Clin. Immunol. 129, 906–920 (2012).

    PubMed  Google Scholar 

  3. Reed, C. E. The natural history of asthma. J. Allergy Clin. Immunol. 118, 543–548 (2006).

    PubMed  Google Scholar 

  4. Licona-Limón, P., Kim, L. K., Palm, N. W. & Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14, 536–542 (2013).

    PubMed  Google Scholar 

  5. Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 15, 271–282 (2015).

    CAS  PubMed  Google Scholar 

  6. Stone, K. D., Prussin, C. & Metcalfe, D. D. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin. Immunol. 125, S73–S80 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Braza, F., Chesne, J., Castagnet, S., Magnan, A. & Brouard, S. Regulatory functions of B cells in allergic diseases. Allergy 69, 1454–1463 (2014).

    CAS  PubMed  Google Scholar 

  8. Noval Rivas, M. & Chatila, T. A. Regulatory T cells in allergic diseases. J. Allergy Clin. Immunol. 138, 639–652 (2016).

    CAS  PubMed  Google Scholar 

  9. Ober, C. & Yao, T.-C. The genetics of asthma and allergic disease: a 21st century perspective. Immunol. Rev. 242, 10–30 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Okada, H., Kuhn, C., Feillet, H. & Bach, J.-F. The 'hygiene hypothesis' for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Cabieses, B., Uphoff, E., Pinart, M., Antó, J. M. & Wright, J. A systematic review on the development of asthma and allergic diseases in relation to international immigration: the leading role of the environment confirmed. PLoS ONE 9, e105347 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Kuehni, C. E., Strippoli, M.-P. F., Low, N. & Silverman, M. Asthma in young south Asian women living in the United Kingdom: the importance of early life. Clin. Exp. Allergy 37, 47–53 (2007).

    CAS  PubMed  Google Scholar 

  13. Hjern, A., Rasmussen, F. & Hedlin, G. Age at adoption, ethnicity and atopic disorder: a study of internationally adopted young men in Sweden. Pediatr. Allergy Immunol. 10, 101–106 (1999).

    CAS  PubMed  Google Scholar 

  14. Bantz, S. K., Zhu, Z. & Zheng, T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J. Clin. Cell. Immunol. 5, 202 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Liang, Y., Chang, C. & Lu, Q. The genetics and epigenetics of atopic dermatitis — filaggrin and other polymorphisms. Clin. Rev. Allergy Immunol. 51, 315–328 (2016).

    CAS  PubMed  Google Scholar 

  16. Heratizadeh, A., Wichmann, K. & Werfel, T. Food allergy and atopic dermatitis: how are they connected? Curr. Allergy Asthma Rep. 11, 284–291 (2011).

    CAS  PubMed  Google Scholar 

  17. Lack, G., Fox, D., Northstone, K. & Golding, J. Factors associated with the development of peanut allergy in childhood. N. Engl. J. Med. 348, 977–985 (2003).

    PubMed  Google Scholar 

  18. Brough, H. A. et al. Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy. J. Allergy Clin. Immunol. 135, 164–170 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Strid, J., Sobolev, O., Zafirova, B., Polic, B. & Hayday, A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–1297 (2011).

    CAS  PubMed  Google Scholar 

  20. Noti, M. et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis. J. Allergy Clin. Immunol. 133, 1390–1399 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Muto, T. et al. The role of basophils and proallergic cytokines, TSLP and IL-33, in cutaneously sensitized food allergy. Int. Immunol. 26, 539–549 (2014). References 19–21 show that cutaneous antigen exposure through damaged skin promotes allergic sensitization through the release of the stress response mediators RAE1 and TSLP, resulting in the recruitment of basophils that promote a T H 2 cell-skewing environment.

    CAS  PubMed  Google Scholar 

  22. Strid, J., Hourihane, J., Kimber, I., Callard, R. & Strobel, S. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin. Exp. Allergy 35, 757–766 (2005).

    CAS  PubMed  Google Scholar 

  23. Holt, P. G., Batty, J. E. & Turner, K. J. Inhibition of specific IgE responses in mice by pre-exposure to inhaled antigen. Immunology 42, 409–417 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cording, S. et al. The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. Mucosal Immunol. 7, 359–368 (2014). This paper demonstrates that the microbiota imprint long-lasting tolerogenic properties on the stromal cells of intestine-draining lymph nodes, thus promoting the generation of T reg cells in response to foreign antigen administration.

    CAS  PubMed  Google Scholar 

  25. Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, Y. & McCusker, C. Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens. J. Allergy Clin. Immunol. 118, 143–151 (2006).

    CAS  PubMed  Google Scholar 

  27. Verhasselt, V. et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat. Med. 14, 170–175 (2008). This paper shows that oral exposure to antigen via breast milk can promote tolerogenic responses that extend into adulthood in mice, and that this is dependent on exposure to TGFβ but not immunoglobulins in the mother's breast milk.

    CAS  PubMed  Google Scholar 

  28. Turfkruyer, M. et al. Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency. Mucosal Immunol. 9, 479–491 (2016). This paper demonstrates that 1-week-old mice have an impaired ability to generate oral tolerogenic responses owing to a deficiency in circulating retinol. The authors show that supplementing vitamin A levels is sufficient to increase the efficiency of oral tolerance.

    CAS  PubMed  Google Scholar 

  29. Michael, H. et al. TGF-β-mediated airway tolerance to allergens induced by peptide-based immunomodulatory mucosal vaccination. Mucosal Immunol. 8, 1248–1261 (2015).

    CAS  PubMed  Google Scholar 

  30. Koplin, J. J. & Allen, K. J. Optimal timing for solids introduction — why are the guidelines always changing? Clin. Exp. Allergy 43, 826–834 (2013).

    CAS  PubMed  Google Scholar 

  31. Perkin, M. R. et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N. Engl. J. Med. 374, 1733–1743 (2016).

    CAS  PubMed  Google Scholar 

  32. Du Toit, G. et al. Effect of avoidance on peanut allergy after early peanut consumption. N. Engl. J. Med. 374, 1435–1443 (2016).

    CAS  PubMed  Google Scholar 

  33. Du Toit, G. et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N. Engl. J. Med. 372, 803–813 (2015). References 31–33 demonstrate that delaying the introduction of potentially allergenic foods to infants increases the risk of allergic sensitization later in childhood.

    CAS  PubMed  Google Scholar 

  34. Turati, F. et al. Early weaning is beneficial to prevent atopic dermatitis occurrence in young children. Allergy 71, 878–888 (2016).

    CAS  PubMed  Google Scholar 

  35. Lynch, S. V. et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J. Allergy Clin. Immunol. 134, 593–601.e12 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. von Mutius, E. & Vercelli, D. Farm living: effects on childhood asthma and allergy. Nat. Rev. Immunol. 10, 861–868 (2010).

    CAS  PubMed  Google Scholar 

  38. Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).

    CAS  PubMed  Google Scholar 

  39. Fujimura, K. E. et al. Man's best friend? The effect of pet ownership on house dust microbial communities. J. Allergy Clin. Immunol. 126, 410–412.e3 (2010).

    PubMed  PubMed Central  Google Scholar 

  40. Lauener, R. P. et al. Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360, 465–466 (2002).

    CAS  PubMed  Google Scholar 

  41. Ege, M. J. et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 117, 817–823 (2006).

    PubMed  Google Scholar 

  42. Medvedev, A. E. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J. Interferon Cytokine Res. 33, 467–484 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ege, M. J. et al. Not all farming environments protect against the development of asthma and wheeze in children. J. Allergy Clin. Immunol. 119, 1140–1147 (2007).

    PubMed  Google Scholar 

  44. Stein, M. M. et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N. Engl. J. Med. 375, 411–421 (2016). This paper compares the household dust endotoxin levels in two human populations, and finds that exposure to high endotoxin levels is associated with protection against allergic sensitization and asthma. The authors demonstrate that the administration to mice of the house dust extract from the homes of people with lower rates of allergic sensitization, but not of the dust from the homes of people with higher rates of allergic sensitization, can protect against allergic airway inflammation in a MYD88-dependent and TRIF-dependent manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Fujimura, K. E. et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc. Natl Acad. Sci. USA 111, 805–810 (2014).

    CAS  PubMed  Google Scholar 

  47. Rodríguez, J. M. et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb. Ecol. Health Dis. 26, 26050 (2015).

    PubMed  Google Scholar 

  48. Fujimura, K. E. & Lynch, S. V. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe 17, 592–602 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Noverr, M. C. & Huffnagle, G. B. The 'microflora hypothesis' of allergic diseases. Clin. Exp. Allergy 35, 1511–1520 (2005).

    CAS  PubMed  Google Scholar 

  50. Bisgaard, H. et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J. Allergy Clin. Immunol. 128, 646–652.e5 (2011).

    PubMed  Google Scholar 

  51. Abrahamsson, T. R. et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin. Exp. Allergy 44, 842–850 (2014).

    CAS  PubMed  Google Scholar 

  52. Ismail, I. H. et al. Early gut colonization by Bifidobacterium breve and B. catenulatum differentially modulates eczema risk in children at high risk of developing allergic disease. Pediatr. Allergy Immunol. 27, 838–846 (2016).

    PubMed  Google Scholar 

  53. Arrieta, M.-C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015).

    PubMed  Google Scholar 

  54. Fujimura, K. E. et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med. 22, 1187–1191 (2016). References 53 and 54 are birth cohort studies that both demonstrate that the microbiota composition and associated changes in faecal and urinary metabolites in the first few months of life are predictive of the development of allergic sensitization and asthma later in childhood.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

    CAS  PubMed  Google Scholar 

  56. Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cahenzli, J., Köller, Y., Wyss, M., Geuking, M. B. & McCoy, K. D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14, 559–570 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Russell, S. L. et al. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4, 158–164 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Johansson, M. E. V. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    CAS  PubMed  Google Scholar 

  64. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  PubMed  Google Scholar 

  65. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  Google Scholar 

  68. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    CAS  PubMed  Google Scholar 

  69. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

    CAS  PubMed  Google Scholar 

  70. Tan, J. et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 15, 2809–2824 (2016).

    CAS  PubMed  Google Scholar 

  71. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014). References 70 and 71 demonstrate that SCFAs produced by the microbiota through the fermentation of dietary fibre protect against allergic inflammation by stimulating RALDH2 activity in CD103+ DCs, which leads to the induction of T reg cells.

    CAS  PubMed  Google Scholar 

  72. Belkaid, Y. & Segre, J. A. Dialogue between skin microbiota and immunity. Science 346, 954–959 (2014).

    CAS  PubMed  Google Scholar 

  73. Sanford, J. A. & Gallo, R. L. Functions of the skin microbiota in health and disease. Semin. Immunol. 25, 370–377 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nakamura, Y. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kong, H. H. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Gollwitzer, E. S. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med. 20, 642–647 (2014).

    CAS  PubMed  Google Scholar 

  77. Herbst, T. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184, 198–205 (2011).

    CAS  PubMed  Google Scholar 

  78. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    PubMed  Google Scholar 

  79. Teo, S. M. et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17, 704–715 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Goldman, D. L. & Huffnagle, G. B. Potential contribution of fungal infection and colonization to the development of allergy. Med. Mycol. 47, 445–456 (2009).

    CAS  PubMed  Google Scholar 

  81. Denning, D. W. The link between fungi and severe asthma: a summary of the evidence. Eur. Respir. J. 27, 615–626 (2006).

    CAS  PubMed  Google Scholar 

  82. Snelgrove, R. J. et al. Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations. J. Allergy Clin. Immunol. 134, 583–592.e6 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Castanhinha, S. et al. Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. J. Allergy Clin. Immunol. 136, 312–322.e7 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sykes, A. & Johnston, S. L. Etiology of asthma exacerbations. J. Allergy Clin. Immunol. 122, 685–688 (2008).

    PubMed  Google Scholar 

  85. Beigelman, A. & Bacharier, L. B. Early-life respiratory infections and asthma development: role in disease pathogenesis and potential targets for disease prevention. Curr. Opin. Allergy Clin. Immunol. 16, 172–178 (2016).

    PubMed  PubMed Central  Google Scholar 

  86. Bisgaard, H. et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ 341, c4978 (2010).

    PubMed  PubMed Central  Google Scholar 

  87. Lynch, J. P. et al. Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity. J. Allergy Clin. Immunol. 138, 1326–1337 (2016).

    CAS  PubMed  Google Scholar 

  88. Siegle, J. S. et al. Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice. Respir. Res. 11, 14 (2010).

    PubMed  PubMed Central  Google Scholar 

  89. Krishnamoorthy, N. et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18, 1525–1530 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Chang, Y.-J. et al. Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J. Clin. Invest. 121, 57–69 (2011).

    CAS  PubMed  Google Scholar 

  91. Deriu, E. et al. Influenza virus affects intestinal microbiota and secondary Salmonella infection in the gut through type I interferons. PLoS Pathog. 12, e1005572 (2016).

    PubMed  PubMed Central  Google Scholar 

  92. Daugule, I., Zavoronkova, J. & Santare, D. Helicobacter pylori and allergy: update of research. World J. Methodol. 5, 203–211 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. Arnold, I. C. et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121, 3088–3093 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Engler, D. B. et al. Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc. Natl Acad. Sci. USA 111, 11810–11815 (2014).

    CAS  PubMed  Google Scholar 

  95. Malaty, H. M. et al. Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood. Lancet 359, 931–935 (2002).

    PubMed  Google Scholar 

  96. Amoah, A. S., Boakye, D. A., van Ree, R. & Yazdanbakhsh, M. Parasitic worms and allergies in childhood: insights from population studies 2008–2013. Pediatr. Allergy Immunol. 25, 208–217 (2014).

    PubMed  Google Scholar 

  97. Stiemsma, L. T., Reynolds, L. A., Turvey, S. E. & Finlay, B. B. The hygiene hypothesis: current perspectives and future therapies. Immunotargets Ther. 4, 143–157 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Allen, J. E. & Maizels, R. M. Diversity and dialogue in immunity to helminths. Nat. Rev. Immunol. 11, 375–388 (2011).

    CAS  PubMed  Google Scholar 

  99. Ahumada, V. et al. IgE responses to Ascaris and mite tropomyosins are risk factors for asthma. Clin. Exp. Allergy 45, 1189–1200 (2015).

    CAS  PubMed  Google Scholar 

  100. Helmby, H. Human helminth therapy to treat inflammatory disorders — where do we stand? BMC Immunol. 16, 12 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Hewitson, J. P., Grainger, J. R. & Maizels, R. M. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol. Biochem. Parasitol. 167, 1–11 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Navarro, S. et al. Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma. Sci. Transl Med. 8, 362ra143 (2016). This paper demonstrates that a secreted hookworm protein, AIP2, can suppress allergic sensitization by stimulating RALDH2 activity in MLN CD103+ DCs, which leads to the induction of T reg cells. The authors show that AIP2 exerts long-term effects on MLNs, which maintain their tolerogenic properties after transfer to recipient mice.

    PubMed  Google Scholar 

  103. Zaiss, M. M. et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 43, 998–1010 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Reynolds, L. A., Finlay, B. B. & Maizels, R. M. Cohabitation in the intestine: interactions among helminth parasites, bacterial microbiota, and host immunity. J. Immunol. 195, 4059–4066 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Sicherer, S. H. & Sampson, H. A. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J. Allergy Clin. Immunol. 133, 291–307 (2014).

    CAS  PubMed  Google Scholar 

  106. Chad, Z. Allergies in children. Paediatr. Child Health 6, 555–566 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bannon, G. A. What makes a food protein an allergen? Curr. Allergy Asthma Rep. 4, 43–46 (2004).

    PubMed  Google Scholar 

  108. 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 

  109. Huby, R. D., Dearman, R. J. & Kimber, I. Why are some proteins allergens? Toxicol. Sci. 55, 235–246 (2000).

    CAS  PubMed  Google Scholar 

  110. Porter, P. et al. Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi. Mucosal Immunol. 2, 504–517 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Brown, C. C. et al. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42, 499–511 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Molenaar, R. et al. Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J. Immunol. 186, 1934–1942 (2011).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge support from their funders. Work in the laboratory of B.B.F. is supported by operating grants from the Canadian Institutes of Health Research (CIHR). B.B.F. is a Canadian Institute for Advanced Research Senior Fellow and the University of British Columbia Peter Wall Distinguished Professor. L.A.R. was supported by postdoctoral fellowship awards from the CIHR and the Michael Smith Foundation for Health Research in partnership with the Allergy, Genes and Environment Network (AllerGen).

Author information

Author notes

  1. Lisa A. Reynolds & B. Brett Finlay

    Present address: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

Authors and Affiliations

  1. Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, V6T 1Z4, British Columbia, Canada

    Lisa A. Reynolds & B. Brett Finlay

  2. Department of Microbiology and Immunology, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    B. Brett Finlay

  3. Present address: Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada.,

    Lisa A. Reynolds & B. Brett Finlay

Authors
  1. Lisa A. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Brett Finlay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Brett Finlay.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Atopic

Describes a state of heightened immune responsiveness to foreign antigens that is mediated by the production of IgE antibodies.

Allergen

A type of antigen that elicits an inappropriate immune response to an otherwise harmless substance.

Airway hyper-reactivity

A typical characteristic of patients with asthma in which the airways constrict in response to a variety of inhaled stimuli. This can be measured in people and in laboratory mice by changes in airway resistance that are induced by inhaled methacholine.

Allergic sensitization

The process of generating antigen-specific IgE antibodies against an allergen.

Lymphocyte anergy

An unresponsive state that can be induced in B cells or T cells that have been chronically stimulated, or when their antigen receptor is stimulated in the absence of co-stimulatory signals.

Regulatory T cell

(Treg cell). A specialized type of CD4+ T cell that suppresses the activity of other immune cells.

Signal transducer and activator of transcription 6

(STAT6). A transcription factor that is required for the differentiation of T helper 2 cells.

Microorganism-associated molecular patterns

(MAMPs). Highly conserved patterns that are found within microbial molecules such as components of bacteria cell walls and are recognized by host innate immune cells through pattern recognition receptors.

Germ-free mice

Mice that are not colonized by any microorganisms and so do not have a microbiota.

Gnotobiotic

Colonized with a known microbiota composition.

Specific pathogen-free mice

(SPF mice). Mice that are free from colonization by particular pathogens but that have a microbiota.

Pathobiont

An organism that can exist as an innocuous member of the microbiota but that in some circumstances can cause pathogenesis.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reynolds, L., Finlay, B. Early life factors that affect allergy development. Nat Rev Immunol 17, 518–528 (2017). https://doi.org/10.1038/nri.2017.39

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2017.39

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