The germless theory of allergic disease: revisiting the hygiene hypothesis

Abstract

Rising rates of allergic disease accompany the healthier benefits of a contemporary westernized lifestyle, such as low infant mortality. It is likely that these twinned phenomena are causally related. The hygiene hypothesis states that allergy and increased longevity are both consequences of reducing infectious stressors during early childhood. Mechanistic explanations for the hygiene hypothesis have typically invoked the T-helper-type 1/2 (TH1/TH2) model. Here, we discuss why we favour a broader 'counter-regulatory' model — one that might also explain the increasing incidence of autoimmune disease in westernized countries.

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Figure 1: Allergy: genes and environment.
Figure 2: Regulators and effectors of TH2 responses.
Figure 3: Schematic view of the counter-regulation hypothesis.

References

  1. 1

    Anonymous. Surveillance for asthma — United States, 1960–1995. Morb. Mort. Wkly Rep. 47, 1–28 (1998).

  2. 2

    Nicolai, T. & von Mutius, E. Pollution and the development of allergy: the East and West Germany story. Arch. Toxicol. Suppl. 19, 201–206 (1997).

    CAS  PubMed  Google Scholar 

  3. 3

    Crater, S. E. & Platts-Mills, T. A. Searching for the cause of the increase in asthma. Curr. Opin. Pediatr. 10, 594–599 (1998).

    CAS  PubMed  Google Scholar 

  4. 4

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

    CAS  Google Scholar 

  5. 5

    Bodner, C., Godden, D. & Seaton, A. Family size, childhood infections and atopic diseases. The Aberdeen WHEASE Group. Thorax 53, 28–32 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Matricardi, P. M. et al. Sibship size, birth order, and atopy in 11,371 Italian young men. J. Allergy Clin. Immunol. 101, 439–444 (1998).

    CAS  PubMed  Google Scholar 

  7. 7

    Ball, T. M. et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N. Engl. J. Med. 343, 538–543 (2000).

    CAS  Google Scholar 

  8. 8

    Kilpelainen, M., Terho, E. O., Helenius, H. & Koskenvuo, M. Farm environment in childhood prevents the development of allergies. Clin. Exp. Allergy 30, 201–208 (2000).

    CAS  PubMed  Google Scholar 

  9. 9

    Downs, S. H. et al. Having lived on a farm and protection against allergic diseases in Australia. Clin. Exp. Allergy 31, 570–575 (2001).

    CAS  PubMed  Google Scholar 

  10. 10

    Forastiere, F. et al. Socioeconomic status, number of siblings, and respiratory infections in early life as determinants of atopy in children. Epidemiology 8, 566–570 (1997).

    CAS  PubMed  Google Scholar 

  11. 11

    Eggleston, P. A. et al. The environment and asthma in U. S. inner cities. Environ. Health Perspect. 107, 439–450 (1999).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Strachan, D. P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55, S2–S10 (2000).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Strachan, D. P., Taylor, E. M. & Carpenter, R. G. Family structure, neonatal infection, and hay fever in adolescence. Arch. Dis. Child. 74, 422–446 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Backman, A., Bjorksten, F., Ilmonen, S., Juntunen, K. & Suoniemi, I. Do infections in infancy affect sensitization to airborne allergens and development of atopic disease? A retrospective study of seven-year-old children. Allergy 39, 309–315 (1984).

    CAS  PubMed  Google Scholar 

  15. 15

    Matricardi, P. M. et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. Br. Med. J. 320, 412–417 (2000).| PubMed |

    CAS  Google Scholar 

  16. 16

    Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J. M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).

    CAS  Google Scholar 

  17. 17

    Aaby, P. et al. Early BCG vaccination and reduction in atopy in Guinea-Bissau. Clin. Exp. Allergy 30, 644–650 (2000).

    CAS  PubMed  Google Scholar 

  18. 18

    Alm, J. S., Lilja, G., Pershagen, G. & Scheynius, A. Early BCG vaccination and development of atopy. Lancet 350, 400–403 (1997).

    CAS  PubMed  Google Scholar 

  19. 19

    Shaheen, S. O. et al. Measles and atopy in Guinea-Bissau. Lancet 347, 1792–1796 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Lewis, S. A. & Britton, J. R. Measles infection, measles vaccination and the effect of birth order in the aetiology of hay fever. Clin. Exp. Allergy 28, 1493–1500 (1998).

    CAS  PubMed  Google Scholar 

  21. 21

    Paunio, M. et al. Measles history and atopic diseases: a population-based cross-sectional study. J. Am. Med. Assoc. 283, 343–346 (2000).

    CAS  Google Scholar 

  22. 22

    Martinez, F. D. Viral infections and the development of asthma. Am. J. Respir. Crit. Care Med. 151, 1644–1647 (1995).

    CAS  PubMed  Google Scholar 

  23. 23

    Busse, W. W. The relationship between viral infections and onset of allergic diseases and asthma. Clin. Exp. Allergy 19, 1–9 (1989).

    CAS  PubMed  Google Scholar 

  24. 24

    Adlerberth, I. et al. Intestinal colonization with Enterobacteriaceae in Pakistani and Swedish hospital-delivered infants. Acta Paediatr. Scand. 80, 602–610 (1991).

    CAS  PubMed  Google Scholar 

  25. 25

    Adlerberth, I. et al. High turnover rate of Escherichia coli strains in the intestinal flora of infants in Pakistan. Epidemiol. Infect. 3, 587–598 (1998). | PubMed |

    Google Scholar 

  26. 26

    Bottcher, M. F., Nordin, E. K., Sandin, A., Midtvedt, T. & Bjorksten, B. Microflora-associated characteristics in faeces from allergic and nonallergic infants. Clin. Exp. Allergy 30, 1590–1596 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

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

    CAS  PubMed  Google Scholar 

  28. 28

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

    CAS  Google Scholar 

  29. 29

    Kalliomaki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076–1079 (2001).

    CAS  Google Scholar 

  30. 30

    Majamaa, H. & Isolauri, E. Probiotics: a novel approach in the management of food allergy. J. Allergy Clin. Immunol. 99, 179–185 (1997).

    CAS  PubMed  Google Scholar 

  31. 31

    Farooqi, I. S. & Hopkin, J. M. Early childhood infection and atopic disorder. Thorax 53, 927–932 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Wickens, K., Pearce, N., Crane, J. & Beasley, R. Antibiotic use in early childhood and the development of asthma. Clin. Exp. Allergy 29, 766–771 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Godfrey, R. C. Asthma and IgE levels in rural and urban communities of The Gambia. Clin. Allergy 5, 201–207 (1975).

    CAS  PubMed  Google Scholar 

  34. 34

    Lynch, N. R. et al. Effect of anthelminthic treatment on the allergic reactivity of children in a tropical slum. J. Allergy Clin. Immunol. 92, 404–411 (1993).

    CAS  PubMed  Google Scholar 

  35. 35

    Barrios, C. et al. Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: predominance of a TH2-biased pattern which persists after adult boosting. Eur. J. Immunol. 26, 1489–1496 (1996).

    CAS  PubMed  Google Scholar 

  36. 36

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

    CAS  PubMed  Google Scholar 

  37. 37

    Prescott, S. L. et al. Reciprocal age-related patterns of allergen-specific T-cell immunity in normal vs. atopic infants. Clin. Exp. Allergy 28, 39–44 (1998).

    CAS  PubMed  Google Scholar 

  38. 38

    Chougnet, C. et al. Influence of human immunodeficiency virus-infected maternal environment on development of infant interleukin-12 production. J. Infect. Dis. 181, 1590–1597 (2000).

    CAS  PubMed  Google Scholar 

  39. 39

    Erb, K. J., Kirman, J., Delahunt, B., Moll, H. & Le Gros, G. Infection of mice with Mycobacterium bovis-BCG induces both TH1 and TH2 immune responses in the absence of interferon-γ signalling. Eur. Cytokine Netw. 10, 147–154 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Arkwright, P. D. & David, T. J. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J. Allergy Clin. Immunol. 107, 531–534 (2001).

    CAS  PubMed  Google Scholar 

  41. 41

    Griffin, D. E. & Ward, B. J. Differential CD4 T cell activation in measles. J. Infect. Dis. 168, 275–281 (1993).

    CAS  PubMed  Google Scholar 

  42. 42

    Atabani, S. F. et al. Natural measles causes prolonged suppression of interleukin-12 production. J. Infect. Dis. 184, 1–9 (2001).

    CAS  PubMed  Google Scholar 

  43. 43

    Wang, C. C., Nolan, T. J., Schad, G. A. & Abraham, D. Infection of mice with the helminth Strongyloides stercoralis suppresses pulmonary allergic responses to ovalbumin. Clin. Exp. Allergy 31, 495–503 (2001).

    CAS  PubMed  Google Scholar 

  44. 44

    Hansen, G., Berry, G, DeKruyff, R. H. & Umetsu, D. T. Allergen-specific TH1 cells fail to counterbalance TH2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Bryan, S. A. et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic repsonse. Lancet 356, 2149–2153 (2000).

    CAS  Google Scholar 

  46. 46

    Larrick, J. W. et al. Does hyperimmunoglobulinemia-E protect tropical populations from allergic disease? J. Allergy Clin. Immunol. 71, 184–188 (1983).

    CAS  PubMed  Google Scholar 

  47. 47

    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  Google Scholar 

  48. 48

    King, C. L. et al. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J. Immunol. 156, 4715–4721 (1996).

    CAS  PubMed  Google Scholar 

  49. 49

    Cooper, P. J., Espinel, I., Paredes, W., Guderian, R. H. & Nutman, T. B. Impaired tetanus-specific cellular and humoral responses following tetanus vaccination in human onchocerciasis: a possible role for interleukin-10. J. Infect. Dis. 178, 1133–1138 (1998).

    CAS  PubMed  Google Scholar 

  50. 50

    Yazdanbakhsh, M., van den Biggerlaar, A. & Maizels, R. M. TH2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease. Trends Immunol. 22, 372–377 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Gara, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Moritani, M. et al. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int. Immunol. 6, 1927–1936 (1994).

    CAS  PubMed  Google Scholar 

  53. 53

    Cannella, B., Gao, Y. L., Brosnan, C. & Raine, C. S. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J. Neurosci. Res. 45, 735–746 (1996).

    CAS  Google Scholar 

  54. 54

    Berg, D. J. et al. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J. Clin. Invest. 96, 2339–2347 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Hoffmann, K. F., Cheever, A. W. & Wynn, T. A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol. 164, 6406–6416 (2000).

    CAS  PubMed  Google Scholar 

  56. 56

    Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).

    CAS  Google Scholar 

  57. 57

    Suzuki, Y. et al. IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii. J. Immunol. 164, 5375–5382 (2000).

    CAS  PubMed  Google Scholar 

  58. 58

    Lamblin, C., Desreumaux, P., Colombel, J. F., Tonnel, A. B. & Wallaert, B. Overexpression of IL-10 mRNA in gut mucosa of patients with allergic asthma. J. Allergy Clin. Immunol. 107, 739–741 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Robinson, D. S. et al. Increased interleukin-10 messenger RNA expression in atopic allergy and asthma. Am. J. Respir. Cell Mol. Biol. 14, 113–117 (1996).

    CAS  PubMed  Google Scholar 

  60. 60

    Borish, L. et al. Interleukin-10 regulation in normal subjects and patients with asthma. J. Allergy Clin. Immunol. 97, 1288–1296 (1996).

    CAS  Google Scholar 

  61. 61

    Hobbs, K., Negri, J., Klinnert, M., Rosenwasser, L. J. & Borish, L. Interleukin-10 and transforming growth factor-β promoter polymorphisms in allergies and asthma. Am. J. Respir. Crit. Care Med. 158, 1958–1962 (1998).

    CAS  PubMed  Google Scholar 

  62. 62

    Zuany-Amorim, C. et al. Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J. Clin. Invest. 95, 2644–2651 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med. 185, 1089–1099 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Makela, M. J. et al. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. Proc. Natl Acad. Sci. USA 97, 6007–6012 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Barnes, P. F. et al. Cytokine production at the site of disease in human tuberculosis. Infect. Immun. 61, 3482–3489 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Kaufmann, S. H., Ladel, C. H. & Flesch, I. E. T cells and cytokines in intracellular bacterial infections: experience with Mycobacterium bovis BCG. CIBA Found. Symp. 195, 123–132 (1995).

    CAS  PubMed  Google Scholar 

  67. 67

    Azim, T. et al. Immune response of children who develop persistent diarrhea following rotavirus infection. Clin. Diagn. Lab. Immunol. 6, 690–695 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Raqib, R. et al. Persistence of local cytokine production in shigellosis in acute and convalescent stages. Infect. Immun. 63, 289–296 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Braunstein, J., Qiao, L., Autschbach, F., Schurmann, G. & Meuer, S. T cells of the human intestinal lamina propria are high producers of interleukin-10. Gut 41, 215–220 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Iwasaki, A. & Kelsall, B. L. Unique functions of CD11b+, CD8α+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–4890 (2001).

    CAS  Google Scholar 

  71. 71

    Autschbach, F. et al. In situ expression of interleukin-10 in noninflamed human gut and in inflammatory bowel disease. Am. J. Pathol. 153, 121–130 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    CAS  Google Scholar 

  73. 73

    Wilson, A. F., Novey, H. S., Berke, R. A. & Surprenant, E. L. Deposition of inhaled pollen and pollen extract in human airways. N. Engl. J. Med. 288, 1056–1058 (1973).

    CAS  PubMed  Google Scholar 

  74. 74

    Sudo, N. et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J. Immunol. 159, 1739–1745 (1997).

    CAS  Google Scholar 

  75. 75

    Kim, J. H. & Ohsawa, M. Oral tolerance to ovalbumin in mice as a model for detecting modulators of the immunologic tolerance to a specific antigen. Biol. Pharm. Bull. 18, 854–858 (1995).

    CAS  PubMed  Google Scholar 

  76. 76

    Gereda, J. E. et al. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355, 1680–1683 (2000).

    CAS  PubMed  Google Scholar 

  77. 77

    Pessi, T., Sutas, Y., Hurme, M. & Isolauri, E. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin. Exp. Allergy 30, 1804–1808 (2000).

    CAS  PubMed  Google Scholar 

  78. 78

    Matricardi, P. M. & Bonini, S. High microbial turnover rate preventing atopy: a solution to inconsistencies impinging on the hygiene hypothesis? Clin. Exp. Allergy 30, 1506–1510 (2000).

    CAS  PubMed  Google Scholar 

  79. 79

    Schevach, E. M. Certified professionals: CD4+CD25+ suppressor T cells. J. Exp. Med. 193, F41–F45 (2001).

    Google Scholar 

  80. 80

    Cottrez, F., Hurst, S. D., Coffman, R. L. & Groux, H. T regulatory cells 1 inhibit a TH2 specific response in vivo. J. Immunol. 165, 4848–4853 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Stene, L. C. & Nafstad, P. Relation between occurrence of type 1 diabetes and asthma. Lancet 357, 607–608 (2001).

    CAS  PubMed  Google Scholar 

  82. 82

    EURODIAB Substudy 2 Study Group. Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. Diabetologia 43, 47–53 (2000). | PubMed |

  83. 83

    Bingley, P. J., Douek, I. F., Rogers, C. A. & Gale, E. A. Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. Bart's–Oxford Family Study Group. Br. Med. J. 321, 420–424 (2000). | PubMed |

    CAS  Google Scholar 

  84. 84

    McKinney, P. A. et al. Early social mixing and childhood type 1 diabetes mellitus: a case control study in Yorkshire, UK. Diabet. Med. 17, 236–242 (2000).

    CAS  PubMed  Google Scholar 

  85. 85

    Rivas, J. M. & Ullrich, S. E. Systemic suppression of delayed-type hypersensitivity by supernatants from UV-irradiated keratinocytes. An essential role for keratinocyte-derived IL-10. J. Immunol. 149, 3865–3871 (1992).

    CAS  PubMed  Google Scholar 

  86. 86

    Mencken, H. L. in A Mencken Chrestomathy 158 (Knopf, New York, 1949).

    Google Scholar 

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Acknowledgements

M.W.-K. and C.L.K. are supported, in part, by grants from the NIH. The authors thank A. Sher for many stimulating discussions.

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Correspondence to Marsha Wills-Karp.

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DATABASES

LocusLink

IFN-γ

IL-1 receptor antagonist

IL-4

IL-5

IL-10

IL-13

TGF-β

Asthma

Atopic dermatits

Glossary

AEROALLERGEN

Airborne allergens; important in allergic asthma.

ALLERGEN

An environmental antigen that typcially elicits allergic responses in susceptible individuals.

ALLERGY

Clinically evident reactions to ubiquitous allergens reflecting acquired immune responses that are marked, phenotypically, by the presence of allergen-specific IgE, along with mast cell and eosinophil recruitment and/or activation. CD4+ T cells that produce a TH2 profile of cytokines (IL-4, IL-5 and IL-13) are thought to be central to the development of allergic responses.

ASTHMA

A chronic disease of the lung, marked by airway hyper-responsiveness and inflammation. The most common form of the disease, allergic asthma, results from inappropriate immune responses to common allergens in genetically susceptible individuals. Allergic asthma is characterized by infiltration of the airway wall with mast cells, lymphocytes and eosinophils. CD4+ T cells producing TH2 cytokines are thought to have a pivotal role in orchestrating the recruitment and activation of these effector cells of the allergic response.

ATOPY

The propensity for developing allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever, defined operationally by elevations in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.

DELAYED-TYPE HYPERSENSITIVITY

(DTH). A T-cell-mediated immune response marked by monocyte/macrophage infiltration and activation. DTH skin tests have classically been used for the diagnosis of infection with intracellular pathogens such as M. tuberculosis, and as a measure of the vigour of the cellular immune system. Classical DTH responses to intracellular pathogens are thought to depend on CD4+ T cells producing a TH1 profile of cytokines (IFN-γ and TNF-β).

PROBIOTIC

Viable bacteria used therapeutically or prophylactically to colonize the intestine for the purpose of modifying the intestinal microflora in ways presumed to be beneficial to the host.

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Wills-Karp, M., Santeliz, J. & Karp, C. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 1, 69–75 (2001). https://doi.org/10.1038/35095579

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