Review and feature article
The many faces of the hygiene hypothesis

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About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact might confer protection against the development of allergic illnesses. The so-called hygiene hypothesis has ever since undergone numerous more or less subtle modifications by various researchers in the fields of epidemiology, clinical science, and immunology. Three major tracts have developed exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and the effect of both on underlying responses of the innate and adaptive immunity. To date, a truly unifying concept has not yet emerged, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures becomes apparent. These influences are discussed as determinants for a number of complex allergic illnesses in this review, while we attempt to pay attention to the importance of different phenotypes, namely of the asthma syndrome. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future.

Section snippets

Viral infections and asthma

Before examining the role of various viral infections for the inception of asthma and wheeze, we must define the phenotype as precisely as possible. On a chronologic scale, the first phenotype that can be delimited relates to the transient wheeze of infancy, which is manifest in the first 1 to 3 years of life and then disappears.10 Antenatally acquired decrements in lung function, exposure to tobacco smoke through the mother in utero, and low birth weight are likely to causally contribute to

Environmental exposures as intermediary of the hygiene hypothesis

Over recent years, there is accumulating evidence to suggest that not only overt infections of the human body but also environmental exposures to nonviable microbial products might pertain to the hygiene hypothesis. In this context the various exposures of children growing up on farms can be seen as a natural experiment. These children are in fact exposed to a large number of diverse microbial environments in animal sheds and hay lofts and through harvesting activities and certain foods.

Practical implications of the hygiene hypothesis

To date, there are no practical implications that can be deduced from the hygiene hypothesis for the prevention of asthma and allergies. Many authors have been concerned about a potential harm associated with the prescription of antibiotics, and a number of studies found a positive association between antibiotics and asthma. These associations are, however, likely to be attributable to reverse causation. Because in many countries asthma, particularly at a young age, is still treated with

Conclusion

The hygiene hypothesis has seen many modifications by research in epidemiology, clinical science, and immunology. Three major trajectories have been proposed discussing the role of overt viral and bacterial infections, the significance of exposure to microbial compounds in the environment, and the interaction of both with underlying innate and adaptive immune responses. A truly unifying concept is still missing, but various pieces of a jigsaw containing a host's immune response, characteristics

References (117)

  • A. Linneberg et al.

    IgG antibodies against microorganisms and atopic disease in Danish adults: the Copenhagen Allergy Study

    J Allergy Clin Immunol

    (2003)
  • C. Nilsson et al.

    Does early EBV infection protect against IgE sensitization?

    J Allergy Clin Immunol

    (2005)
  • J.S. Alm et al.

    Early BCG vaccination and development of atopy

    Lancet

    (1997)
  • U. Herz et al.

    BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model

    J Allergy Clin Immunol

    (1998)
  • I. Sayers et al.

    Suppression of allergic airway disease using mycobacterial lipoglycans

    J Allergy Clin Immunol

    (2004)
  • J.B.-F.C. Riedler et al.

    Early life exposure to farming provides protection against the development of asthma and allergy

    Lancet

    (2001)
  • R.T. van Strien et al.

    Microbial exposure of rural school children, as assessed by levels of N-acetyl-muramic acid in mattress dust, and its association with respiratory health

    J Allergy Clin Immunol

    (2004)
  • L. Portengen et al.

    Endotoxin exposure and atopic sensitization in adult pig farmers

    J Allergy Clin Immunol

    (2005)
  • W. Eder et al.

    Toll-like receptor 2 as a major gene for asthma in children of European farmers

    J Allergy Clin Immunol

    (2004)
  • T. Kaisho et al.

    Toll-like receptor function and signaling

    J Allergy Clin Immunol

    (2006)
  • R.P. Lauener et al.

    Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children

    Lancet

    (2002)
  • F.D. Martinez et al.

    Role of microbial burden in aetiology of allergy and asthma

    Lancet

    (1999)
  • R.S. Geha et al.

    The regulation of immunoglobulin E class-switch recombination

    Nat Rev Immunol

    (2003)
  • T.A. Platts-Mills et al.

    Con: the increase in asthma cannot be ascribed to cleanliness

    Am J Respir Crit Care Med

    (2001)
  • J.F. Bach

    The effect of infections on susceptibility to autoimmune and allergic diseases

    N Engl J Med

    (2002)
  • S.C. Eisenbarth et al.

    Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen

    J Exp Med

    (2002)
  • C. Braun-Fahrlander et al.

    Environmental exposure to endotoxin and its relation to asthma in school-age children

    N Engl J Med

    (2002)
  • C.A. Akdis et al.

    Genes of tolerance

    Allergy

    (2004)
  • Y. Belkaid et al.

    CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity

    Nature

    (2002)
  • F.D. Martinez et al.

    Asthma and wheezing in the first six years of life. The Group Health Medical Associates

    N Engl J Med

    (1995)
  • F.D. Martinez et al.

    Diminished lung function as a predisposing factor for wheezing respiratory illness in infants

    N Engl J Med

    (1988)
  • C. Dezateux et al.

    Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma

    Am J Respir Crit Care Med

    (1999)
  • F. Rusconi et al.

    Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group

    Am J Respir Crit Care Med

    (1999)
  • P. Nafstad et al.

    Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort

    Pediatrics

    (2005)
  • S. Illi et al.

    Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study

    BMJ

    (2001)
  • T. Ball et al.

    Siblings, day-care attendance, and the risk of asthma and wheezing during childhood

    N Engl J Med

    (2000)
  • J.C. Celedon et al.

    Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years

    Am J Respir Crit Care Med

    (2003)
  • R.J. Kurukulaaratchy et al.

    Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease

    Allergy

    (2005)
  • H.J. Wassall et al.

    A comparison of virus-associated and multi-trigger wheeze in school children

    J Asthma

    (2005)
  • E. von Mutius et al.

    Frequency of infections in the first years of life and risk of asthma, atopy and airway hyperresponsiveness among schoolage children

    Eur Respir J

    (1999)
  • M. Calvani et al.

    Fever episodes in early life and the development of atopy in children with asthma

    Eur Respir J

    (2002)
  • J.C. Celedon et al.

    Day care attendance, respiratory tract illnesses, wheezing, asthma, and total serum IgE level in early childhood

    Arch Pediatr Adolesc Med

    (2002)
  • S. Johnston et al.

    Community study of role of viral infections in exacerbations of asthma in 9-11 year old children

    BMJ

    (1995)
  • J. Henderson et al.

    Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study

    Pediatr Allergy Immunol

    (2005)
  • M.E. Dahl et al.

    Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells

    Nat Immunol

    (2004)
  • A. Dakhama et al.

    Virus-induced airway dysfunction: pathogenesis and biomechanisms

    Pediatr Infect Dis J

    (2005)
  • L.A. Rosenthal et al.

    Attenuated innate mechanisms of interferon-gamma production in rats susceptible to postviral airway dysfunction

    Am J Respir Cell Mol Biol

    (2004)
  • L.D. Mikus et al.

    Reduced interferon-gamma secretion by natural killer cells from rats susceptible to postviral chronic airway dysfunction

    Am J Respir Cell Mol Biol

    (2001)
  • S.L. Prescott et al.

    The value of perinatal immune responses in predicting allergic disease at 6 years of age

    Allergy

    (2003)
  • S. Muthukkumar et al.

    The ability of B cells and dendritic cells to present antigen increases during ontogeny

    J Immunol

    (2000)

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    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editor: Harold S. Nelson, MD

    Disclosure of potential conflict of interest: R. Lauener has consultant arrangements with Phadia, Sweden and Novartis, Switzerland; and has grants/research support from the Swiss National Research Foundation, European Union, and Kuhne-Foundation. E. von Mutius has consultant arrangements with GlaxoSmithKline and UCB and is employed by Ludwig Maximilian University Munich. B. Schaub has declared that she has no conflict of interest.

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