Anagnostou, K., Meyer, R., Fox, A. & Shah, N. The rapidly changing world of food allergy in children. F1000Prime Rep. 7, 35 (2015).
Burks, A. W. et al. ICON: food allergy. J. Allergy Clin. Immunol. 129, 906–920 (2012).
Reed, C. E. The natural history of asthma. J. Allergy Clin. Immunol. 118, 543–548 (2006).
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).
Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 15, 271–282 (2015).
Stone, K. D., Prussin, C. & Metcalfe, D. D. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin. Immunol. 125, S73–S80 (2010).
Braza, F., Chesne, J., Castagnet, S., Magnan, A. & Brouard, S. Regulatory functions of B cells in allergic diseases. Allergy 69, 1454–1463 (2014).
Noval Rivas, M. & Chatila, T. A. Regulatory T cells in allergic diseases. J. Allergy Clin. Immunol. 138, 639–652 (2016).
Ober, C. & Yao, T.-C. The genetics of asthma and allergic disease: a 21st century perspective. Immunol. Rev. 242, 10–30 (2011).
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).
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).
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).
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).
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).
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).
Heratizadeh, A., Wichmann, K. & Werfel, T. Food allergy and atopic dermatitis: how are they connected? Curr. Allergy Asthma Rep. 11, 284–291 (2011).
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).
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).
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).
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).
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 TH2 cell-skewing environment.
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).
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).
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 Treg cells in response to foreign antigen administration.
Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).
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).
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.
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.
Michael, H. et al. TGF-β-mediated airway tolerance to allergens induced by peptide-based immunomodulatory mucosal vaccination. Mucosal Immunol. 8, 1248–1261 (2015).
Koplin, J. J. & Allen, K. J. Optimal timing for solids introduction — why are the guidelines always changing? Clin. Exp. Allergy 43, 826–834 (2013).
Perkin, M. R. et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N. Engl. J. Med. 374, 1733–1743 (2016).
Du Toit, G. et al. Effect of avoidance on peanut allergy after early peanut consumption. N. Engl. J. Med. 374, 1435–1443 (2016).
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.
Turati, F. et al. Early weaning is beneficial to prevent atopic dermatitis occurrence in young children. Allergy 71, 878–888 (2016).
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).
Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).
von Mutius, E. & Vercelli, D. Farm living: effects on childhood asthma and allergy. Nat. Rev. Immunol. 10, 861–868 (2010).
Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).
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).
Lauener, R. P. et al. Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360, 465–466 (2002).
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).
Medvedev, A. E. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J. Interferon Cytokine Res. 33, 467–484 (2013).
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).
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.
Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016).
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).
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).
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).
Noverr, M. C. & Huffnagle, G. B. The 'microflora hypothesis' of allergic diseases. Clin. Exp. Allergy 35, 1511–1520 (2005).
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).
Abrahamsson, T. R. et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin. Exp. Allergy 44, 842–850 (2014).
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).
Arrieta, M.-C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015).
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.
Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).
Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).
Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).
Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).
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).
Russell, S. L. et al. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4, 158–164 (2013).
Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).
Johansson, M. E. V. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).
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).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
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).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
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).
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 Treg cells.
Belkaid, Y. & Segre, J. A. Dialogue between skin microbiota and immunity. Science 346, 954–959 (2014).
Sanford, J. A. & Gallo, R. L. Functions of the skin microbiota in health and disease. Semin. Immunol. 25, 370–377 (2013).
Nakamura, Y. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401 (2013).
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).
Gollwitzer, E. S. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med. 20, 642–647 (2014).
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).
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).
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).
Goldman, D. L. & Huffnagle, G. B. Potential contribution of fungal infection and colonization to the development of allergy. Med. Mycol. 47, 445–456 (2009).
Denning, D. W. The link between fungi and severe asthma: a summary of the evidence. Eur. Respir. J. 27, 615–626 (2006).
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).
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).
Sykes, A. & Johnston, S. L. Etiology of asthma exacerbations. J. Allergy Clin. Immunol. 122, 685–688 (2008).
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).
Bisgaard, H. et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ 341, c4978 (2010).
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).
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).
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).
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).
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).
Daugule, I., Zavoronkova, J. & Santare, D. Helicobacter pylori and allergy: update of research. World J. Methodol. 5, 203–211 (2015).
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).
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).
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).
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).
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).
Allen, J. E. & Maizels, R. M. Diversity and dialogue in immunity to helminths. Nat. Rev. Immunol. 11, 375–388 (2011).
Ahumada, V. et al. IgE responses to Ascaris and mite tropomyosins are risk factors for asthma. Clin. Exp. Allergy 45, 1189–1200 (2015).
Helmby, H. Human helminth therapy to treat inflammatory disorders — where do we stand? BMC Immunol. 16, 12 (2015).
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).
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 Treg cells. The authors show that AIP2 exerts long-term effects on MLNs, which maintain their tolerogenic properties after transfer to recipient mice.
Zaiss, M. M. et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 43, 998–1010 (2015).
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).
Sicherer, S. H. & Sampson, H. A. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J. Allergy Clin. Immunol. 133, 291–307 (2014).
Chad, Z. Allergies in children. Paediatr. Child Health 6, 555–566 (2001).
Bannon, G. A. What makes a food protein an allergen? Curr. Allergy Asthma Rep. 4, 43–46 (2004).
Untersmayr, E. & Jensen-Jarolim, E. The role of protein digestibility and antacids on food allergy outcomes. J. Allergy Clin. Immunol. 121, 1301–1308 (2008).
Huby, R. D., Dearman, R. J. & Kimber, I. Why are some proteins allergens? Toxicol. Sci. 55, 235–246 (2000).
Porter, P. et al. Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi. Mucosal Immunol. 2, 504–517 (2009).
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).
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).