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.

The immunology of the allergy epidemic and the hygiene hypothesis

Abstract

The immunology of the hygiene hypothesis of allergy is complex and involves the loss of cellular and humoral immunoregulatory pathways as a result of the adoption of a Western lifestyle and the disappearance of chronic infectious diseases. The influence of diet and reduced microbiome diversity now forms the foundation of scientific thinking on how the allergy epidemic occurred, although clear mechanistic insights into the process in humans are still lacking. Here we propose that barrier epithelial cells are heavily influenced by environmental factors and by microbiome-derived danger signals and metabolites, and thus act as important rheostats for immunoregulation, particularly during early postnatal development. Preventive strategies based on this new knowledge could exploit the diversity of the microbial world and the way humans react to it, and possibly restore old symbiotic relationships that have been lost in recent times, without causing disease or requiring a return to an unhygienic life style.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Protective and risk factors for allergy development in early life.
Figure 2: The epithelium as the rheostat of the allergic response.

References

  1. 1

    Umetsu, D.T., McIntire, J.J., Akbari, O., Macaubas, C. & DeKruyff, R.H. Asthma: an epidemic of dysregulated immunity. Nat. Immunol. 3, 715–720 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2

    Eder, W., Ege, M.J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Platts-Mills, T.A. The allergy epidemics: 1870-2010. J. Allergy Clin. Immunol. 136, 3–13 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Sicherer, S.H., Muñoz-Furlong, A., Godbold, J.H. & Sampson, H.A. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J. Allergy Clin. Immunol. 125, 1322–1326 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6

    Gerrard, J.W., Geddes, C.A., Reggin, P.L., Gerrard, C.D. & Horne, S. Serum IgE levels in white and Metis communities in Saskatchewan. Ann. Allergy 37, 91–100 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Strachan, D.P. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260 (1989).

    CAS  Article  Google Scholar 

  8. 8

    Strachan, D.P. et al. Siblings, asthma, rhinoconjunctivitis and eczema: a worldwide perspective from the International Study of Asthma and Allergies in Childhood. Clin. Exp. Allergy 45, 126–136 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9

    Illi, S. et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. Br. Med. J. 322, 390–395 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Smits, H.H. et al. Microbes and asthma: opportunities for intervention. J. Allergy Clin. Immunol. 137, 690–697 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Feldman, A.S., He, Y., Moore, M.L., Hershenson, M.B. & Hartert, T.V. Toward primary prevention of asthma. Reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma. Am. J. Respir. Crit. Care Med. 191, 34–44 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Rantala, A.K., Jaakkola, M.S., Mäkikyrö, E.M., Hugg, T.T. & Jaakkola, J.J. Early respiratory infections and the development of asthma in the first 27 years of life. Am. J. Epidemiol. 182, 615–623 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13

    Matricardi, P.M., Rosmini, F., Panetta, V., Ferrigno, L. & Bonini, S. Hay fever and asthma in relation to markers of infection in the United States. J. Allergy Clin. Immunol. 110, 381–387 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    McIntire, J.J. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat. Immunol. 2, 1109–1116 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Janse, J.J. et al. The association between foodborne and orofecal pathogens and allergic sensitization—EuroPrevall study. Pediatr. Allergy Immunol. 25, 250–256 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    von Mutius, E. et al. Prevalence of asthma and atopy in two areas of West and East Germany. Am. J. Respir. Crit. Care Med. 149, 358–364 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17

    Strachan, D. et al. Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatr. Allergy Immunol. 8, 161–176 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

    Alberca-Custódio, R.W. et al. Aerobic exercise reduces asthma phenotype by modulation of the leukotriene pathway. Front. Immunol. 7, 237 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19

    Rook, G.A. Hygiene hypothesis and autoimmune diseases. Clin. Rev. Allergy Immunol. 42, 5–15 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20

    Hanski, I. et al. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc. Natl. Acad. Sci. USA 109, 8334–8339 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  22. 22

    Depner, M. et al. Bacterial microbiota of the upper respiratory tract and childhood asthma. J. Allergy Clin. Immunol. 139, 826–834.e13 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23

    Hua, X., Goedert, J.J., Pu, A., Yu, G. & Shi, J. Allergy associations with the adult fecal microbiota: analysis of the American Gut Project. EBioMedicine 3, 172–179 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Lodge, C.J. et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr. 104, 38–53 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25

    Loss, G. et al. Consumption of unprocessed cow's milk protects infants from common respiratory infections. J. Allergy Clin. Immunol. 135, 56–62 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26

    Martin, R. et al. Early-life events, including mode of delivery and type of feeding, siblings and gender, shape the developing gut microbiota. PLoS One 11, e0158498 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27

    Hasegawa, K. et al. Household siblings and nasal and fecal microbiota in infants. Pediatr. Int. 59, 473–481 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Tun, H.M. et al. Exposure to household furry pets influences the gut microbiota of infant at 3-4 months following various birth scenarios. Microbiome 5, 40 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Lambrecht, B.N. & Hammad, H. The immunology of asthma. Nat. Immunol. 16, 45–56 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30

    Pulendran, B. & Artis, D. New paradigms in type 2 immunity. Science 337, 431–435 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Coquet, J.M. et al. Interleukin-21-producing CD4+ T cells promote type 2 immunity to house dust mites. Immunity 43, 318–330 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32

    Hansen, G., Yeung, V.P., Berry, G., Umetsu, D.T. & DeKruyff, R.H. Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18. J. Immunol. 164, 223–230 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33

    Eisenbarth, S.C. et al. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645–1651 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Bacher, P. et al. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167, 1067–1078.e16 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35

    Stephens, R., Randolph, D.A., Huang, G., Holtzman, M.J. & Chaplin, D.D. Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral infection-induced allergic asthma. J. Immunol. 169, 5458–5467 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36

    van den Biggelaar, A.H. et al. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356, 1723–1727 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37

    Schmiedel, Y. et al. CD4+CD25hiFOXP3+ regulatory T cells and cytokine responses in human schistosomiasis before and after treatment with praziquantel. PLoS Negl. Trop. Dis. 9, e0003995 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38

    Wilson, M.S. et al. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J. Exp. Med. 202, 1199–1212 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Smits, H.H. et al. Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection. J. Allergy Clin. Immunol. 120, 932–940 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40

    van der Vlugt, L.E.P.M. et al. Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function. Int. J. Parasitol. 47, 545–554 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Holt, P.G. et al. Distinguishing benign from pathologic TH2 immunity in atopic children. J. Allergy Clin. Immunol. 137, 379–387 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    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  Article  Google Scholar 

  43. 43

    Geuking, M.B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Navarro, S. et al. The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways. Mucosal Immunol. 4, 53–65 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48

    Lluis, A. et al. Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood. J. Allergy Clin. Immunol. 133, 551–559 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49

    Schaub, B. et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J. Allergy Clin. Immunol. 123, 774–782 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50

    Schröder, P.C. et al. A switch in regulatory T cells through farm exposure during immune maturation in childhood. Allergy 72, 604–615 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51

    Akdis, C.A. et al. Induction and differential regulation of bee venom phospholipase A2-specific human IgE and IgG4 antibodies in vitro requires allergen-specific and nonspecific activation of T and B cells. J. Allergy Clin. Immunol. 99, 345–353 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52

    Mitre, E., Norwood, S. & Nutman, T.B. Saturation of immunoglobulin E (IgE) binding sites by polyclonal IgE does not explain the protective effect of helminth infections against atopy. Infect. Immun. 73, 4106–4111 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    van de Veen, W. et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J. Allergy Clin. Immunol. 131, 1204–1212 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54

    Strait, R.T., Morris, S.C. & Finkelman, F.D. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J. Clin. Invest. 116, 833–841 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Tyagi, N. et al. Comparisons of allergenic and metazoan parasite proteins: allergy the price of immunity. PLOS Comput. Biol. 11, e1004546 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56

    Amoah, A.S. et al. Peanut-specific IgE antibodies in asymptomatic Ghanaian children possibly caused by carbohydrate determinant cross-reactivity. J. Allergy Clin. Immunol. 132, 639–647 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Valmonte, G.R., Cauyan, G.A. & Ramos, J.D. IgE cross-reactivity between house dust mite allergens and Ascaris lumbricoides antigens. Asia Pac. Allergy 2, 35–44 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Patel, P.S., King, R.G. & Kearney, J.F. Pulmonary α-1,3-glucan-specific IgA-secreting B cells suppress the development of cockroach allergy. J. Immunol. 197, 3175–3187 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Patel, P.S. & Kearney, J.F. Neonatal exposure to pneumococcal phosphorylcholine modulates the development of house dust mite allergy during adult life. J. Immunol. 194, 5838–5850 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Kin, N.W., Stefanov, E.K., Dizon, B.L. & Kearney, J.F. Antibodies generated against conserved antigens expressed by bacteria and allergen-bearing fungi suppress airway disease. J. Immunol. 189, 2246–2256 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Kearney, J.F., Patel, P., Stefanov, E.K. & King, R.G. Natural antibody repertoires: development and functional role in inhibiting allergic airway disease. Annu. Rev. Immunol. 33, 475–504 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63

    Deckers, J. et al. Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4-dependent dermal dendritic cells. J. Allergy Clin. Immunol. (2017).

  64. 64

    Halim, T.Y. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

    de Heer, H.J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    McGuirk, P., McCann, C. & Mills, K.H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J. Exp. Med. 195, 221–231 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Smits, H.H. et al. Cholera toxin B suppresses allergic inflammation through induction of secretory IgA. Mucosal Immunol. 2, 331–339 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69

    Hammad, H. & Lambrecht, B.N. Barrier epithelial cells and the control of type 2 immunity. Immunity 43, 29–40 (2015).

    CAS  Article  Google Scholar 

  70. 70

    Hammad, H. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15, 410–416 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Guo, L. et al. Innate immunological function of TH2 cells in vivo. Nat. Immunol. 16, 1051–1059 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Van Dyken, S.J. et al. A tissue checkpoint regulates type 2 immunity. Nat. Immunol. 17, 1381–1387 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    Lloyd, C.M. & Marsland, B.J. Lung homeostasis: influence of age, microbes, and the immune system. Immunity 46, 549–561 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

    de Kleer, I.M. et al. Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. Immunity 45, 1285–1298 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75

    Steer, C.A. et al. Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization. J. Allergy Clin. Immunol. 140, 593–595 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76

    Saluzzo, S. et al. First-breath-induced type 2 pathways shape the lung immune environment. Cell Rep. 18, 1893–1905 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78

    Braun-Fahrländer, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  79. 79

    Loss, G.J. et al. The early development of wheeze. Environmental determinants and genetic susceptibility at 17q21. Am. J. Respir. Crit. Care Med. 193, 889–897 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80

    House, J.S. et al. Early-life farm exposures and adult asthma and atopy in the Agricultural Lung Health Study. J. Allergy Clin. Immunol. 140, 249–256 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  81. 81

    Stein, M.M. et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N. Engl. J. Med. 375, 411–421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Schuijs, M.J. et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349, 1106–1110 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83

    Wang, J., Ouyang, Y., Guner, Y., Ford, H.R. & Grishin, A.V. Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes. J. Immunol. 183, 1384–1392 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Brand, S. et al. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J. Allergy Clin. Immunol. 128, 618–625 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85

    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  Article  Google Scholar 

  86. 86

    McFarlane, A.J. et al. Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota. J. Allergy Clin. Immunol. (in the press).

  87. 87

    McSorley, H.J., Blair, N.F., Smith, K.A., McKenzie, A.N. & Maizels, R.M. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 7, 1068–1078 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Melendez, A.J. et al. Inhibition of FcɛRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat. Med. 13, 1375–1381 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89

    Rzepecka, J. et al. The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype. Int. J. Parasitol. 43, 211–223 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    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  Article  PubMed Central  Google Scholar 

  91. 91

    Daniłowicz-Luebert, E. et al. A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation. Int. J. Parasitol. 43, 201–210 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  92. 92

    McSorley, H.J. et al. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur. J. Immunol. 42, 2667–2682 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Ebner, F. et al. Therapeutic potential of larval excretory/secretory proteins of the pig whipworm Trichuris suis in allergic disease. Allergy 69, 1489–1497 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94

    Park, S.K. et al. Macrophage migration inhibitory factor homologs of anisakis simplex suppress Th2 response in allergic airway inflammation model via CD4+CD25+Foxp3+ T cell recruitment. J. Immunol. 182, 6907–6914 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95

    Park, H.K. et al. Macrophage migration inhibitory factor isolated from a parasite inhibited Th2 cytokine production in PBMCs of atopic asthma patients. J. Asthma 49, 10–15 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96

    Navarro, S. et al. Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma. Sci. Transl. Med. 8, 362ra143 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

B.N.L. and H.H. are supported by Ghent University (Concerted Research Initiative (GOA) grant) and by the Scientific Research Foundation Flanders (FWO).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Bart N Lambrecht or Hamida Hammad.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lambrecht, B., Hammad, H. The immunology of the allergy epidemic and the hygiene hypothesis. Nat Immunol 18, 1076–1083 (2017). https://doi.org/10.1038/ni.3829

Download citation

Further reading

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