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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Anonymous. Surveillance for asthma — United States, 1960–1995. Morb. Mort. Wkly Rep. 47, 1–28 (1998).
Nicolai, T. & von Mutius, E. Pollution and the development of allergy: the East and West Germany story. Arch. Toxicol. Suppl. 19, 201–206 (1997).
Crater, S. E. & Platts-Mills, T. A. Searching for the cause of the increase in asthma. Curr. Opin. Pediatr. 10, 594–599 (1998).
Strachan, D. P. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260 (1989). | PubMed |
Bodner, C., Godden, D. & Seaton, A. Family size, childhood infections and atopic diseases. The Aberdeen WHEASE Group. Thorax 53, 28–32 (1998).
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).
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).
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).
Downs, S. H. et al. Having lived on a farm and protection against allergic diseases in Australia. Clin. Exp. Allergy 31, 570–575 (2001).
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).
Eggleston, P. A. et al. The environment and asthma in U. S. inner cities. Environ. Health Perspect. 107, 439–450 (1999).
Strachan, D. P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55, S2–S10 (2000).
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).
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).
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 |
Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J. M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).
Aaby, P. et al. Early BCG vaccination and reduction in atopy in Guinea-Bissau. Clin. Exp. Allergy 30, 644–650 (2000).
Alm, J. S., Lilja, G., Pershagen, G. & Scheynius, A. Early BCG vaccination and development of atopy. Lancet 350, 400–403 (1997).
Shaheen, S. O. et al. Measles and atopy in Guinea-Bissau. Lancet 347, 1792–1796 (1996).
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).
Paunio, M. et al. Measles history and atopic diseases: a population-based cross-sectional study. J. Am. Med. Assoc. 283, 343–346 (2000).
Martinez, F. D. Viral infections and the development of asthma. Am. J. Respir. Crit. Care Med. 151, 1644–1647 (1995).
Busse, W. W. The relationship between viral infections and onset of allergic diseases and asthma. Clin. Exp. Allergy 19, 1–9 (1989).
Adlerberth, I. et al. Intestinal colonization with Enterobacteriaceae in Pakistani and Swedish hospital-delivered infants. Acta Paediatr. Scand. 80, 602–610 (1991).
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 |
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).
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).
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).
Kalliomaki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076–1079 (2001).
Majamaa, H. & Isolauri, E. Probiotics: a novel approach in the management of food allergy. J. Allergy Clin. Immunol. 99, 179–185 (1997).
Farooqi, I. S. & Hopkin, J. M. Early childhood infection and atopic disorder. Thorax 53, 927–932 (1998).
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).
Godfrey, R. C. Asthma and IgE levels in rural and urban communities of The Gambia. Clin. Allergy 5, 201–207 (1975).
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).
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).
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).
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).
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).
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).
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).
Griffin, D. E. & Ward, B. J. Differential CD4 T cell activation in measles. J. Infect. Dis. 168, 275–281 (1993).
Atabani, S. F. et al. Natural measles causes prolonged suppression of interleukin-12 production. J. Infect. Dis. 184, 1–9 (2001).
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).
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).
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).
Larrick, J. W. et al. Does hyperimmunoglobulinemia-E protect tropical populations from allergic disease? J. Allergy Clin. Immunol. 71, 184–188 (1983).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Borish, L. et al. Interleukin-10 regulation in normal subjects and patients with asthma. J. Allergy Clin. Immunol. 97, 1288–1296 (1996).
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).
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).
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).
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).
Barnes, P. F. et al. Cytokine production at the site of disease in human tuberculosis. Infect. Immun. 61, 3482–3489 (1993).
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).
Azim, T. et al. Immune response of children who develop persistent diarrhea following rotavirus infection. Clin. Diagn. Lab. Immunol. 6, 690–695 (1999).
Raqib, R. et al. Persistence of local cytokine production in shigellosis in acute and convalescent stages. Infect. Immun. 63, 289–296 (1995).
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).
Iwasaki, A. & Kelsall, B. L. Unique functions of CD11b+, CD8α+, and double-negative Peyer's patch dendritic cells. J. Immunol. 166, 4884–4890 (2001).
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).
Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
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).
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).
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).
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).
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).
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).
Schevach, E. M. Certified professionals: CD4+CD25+ suppressor T cells. J. Exp. Med. 193, F41–F45 (2001).
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).
Stene, L. C. & Nafstad, P. Relation between occurrence of type 1 diabetes and asthma. Lancet 357, 607–608 (2001).
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 |
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 |
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).
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).
Mencken, H. L. in A Mencken Chrestomathy 158 (Knopf, New York, 1949).
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.
Airborne allergens; important in allergic asthma.
An environmental antigen that typcially elicits allergic responses in susceptible individuals.
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.
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.
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).
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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