REVIEW ARTICLES
The role of endotoxin and its receptors in allergic disease

https://doi.org/10.1016/S1081-1206(10)60983-0Get rights and content

Objectives

To summarize the existing literature on the association of endotoxin with respiratory diseases and allergic sensitization and to review the potentially modifying effects of endotoxin receptor polymorphisms.

Data Sources

English-language articles were identified from the MEDLINE and PubMed databases using combinations of the following search terms: endotoxin, toll-like receptor, polymorphisms, atopy, asthma, and allergy. Other sources included experts in the field and the bibliographies of pertinent articles.

Study Selection

Relevant articles were selected based on the authors' expert opinion.

Results

Cross-sectional studies, particularly those of children raised in rural European communities, suggest that early endotoxin exposure may protect against the development of allergic sensitization and atopic asthma. However, endotoxin exposure may also contribute to other nonatopic respiratory disorders and may exacerbate disease in individuals with preexisting asthma. Paradoxically, among individuals exposed to high levels of endotoxin, carriers of a functional mutation in toll-like receptor 4, which reduces cellular responsiveness to endotoxin, may be at lower risk of developing allergic sensitization.

Conclusions

The effect of endotoxin exposure on allergic sensitization and asthma appears to be influenced by the timing of exposure, the presence or absence of preexisting disease, and polymorphisms in the genes that encode endotoxin receptors. Further studies are needed to define the window period for this effect, as well as the underlying immunologic mechanism.

REFERENCES (88)

  • T Kawai et al.

    Unrespon-siveness of MyD88-deficient mice to endotoxin

    Immunity.

    (1999)
  • RP Lauener et al.

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

    Lancet.

    (2002)
  • JG Woo et al.

    The −159 C → T polymorphism of CD14 is associated with nonatopic asthma and food allergy

    J Allergy Clin Immunol.

    (2003)
  • O Michel et al.

    Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings

    J Allergy Clin Immunol.

    (2003)
  • M Werner et al.

    TLR4 gene variants modify endotoxin effects on asthma

    J Allergy Clin Immunol.

    (2003)
  • TJ Kang et al.

    Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients

    FEMS Immunol Med Microbiol.

    (2001)
  • TJ Kang et al.

    A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy

    Cytokine.

    (2002)
  • P Ahmad-Nejad et al.

    The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype

    J Allergy Clin Immunol.

    (2004)
  • W Eder et al.

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

    J Allergy Clin Immunol.

    (2004)
  • S Romagnani

    Induction of TH1 and TH2 responses: a key role for the 'natural' immune response?

    Immunol Today.

    (1992)
  • FD Martinez et al.

    Role of microbial burden in aetiology of allergy and asthma

    Lancet.

    (1999)
  • MK Tulic et al.

    Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults

    Lancet.

    (2004)
  • DM Mannino et al.

    Surveillance for asthma: United States, 1960–1995

    MMWR Morb Mortal Wkly Rep.

    (1998)
  • DP Strachan

    Hay fever, hygiene, and household size

    BMJ.

    (1989)
  • PM Matricardi et al.

    Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus

    BMJ.

    (1997)
  • FD Martinez et al.

    Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels

    Thorax.

    (1995)
  • S Illi et al.

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

    BMJ.

    (2001)
  • C Braun-Fahrlander et al.

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

    N Engl J Med.

    (2002)
  • U Gehring et al.

    House dust endotoxin and allergic sensitization in children

    Am J Respir Crit Care Med.

    (2002)
  • R Rylander et al.

    Pulmonary function and symptoms after inhalation of endotoxin

    Am Rev Respir Dis.

    (1989)
  • O Michel et al.

    Dose-response relationship to inhaled endotoxin in normal subjects

    Am J Respir Crit Care Med.

    (1997)
  • R Rylander et al.

    Endotoxin in cotton dust and respiratory function decrement among cotton workers in an experimental cardroom

    Am Rev Respir Dis.

    (1985)
  • RM Castellan et al.

    Inhaled endotoxin and decreased spirometric values: an exposure-response relation for cotton dust

    N Engl J Med.

    (1987)
  • DA Schwartz et al.

    The role of endotoxin in grain dust-induced lung disease

    Am J Respir Crit Care Med.

    (1995)
  • JA Nightingale et al.

    Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects

    Thorax.

    (1998)
  • B Beutler et al.

    Innate immune sensing and its roots: the story of endotoxin

    Nat Rev Immunol.

    (2003)
  • DT Chun et al.

    Second inter-laboratory study comparing endotoxin assay results from cotton dust

    Ann Agric Environ Med.

    (2002)
  • C Braun-Fahrlander et al.

    Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community: SCARPOL team (Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution)

    Clin Exp Allergy.

    (1999)
  • OS von Ehrenstein et al.

    Reduced risk of hay fever and asthma among children of farmers

    Clin Exp Allergy.

    (2000)
  • M Kilpelainen et al.

    Farm environment in childhood prevents the development of allergies

    Clin Exp Allergy.

    (2000)
  • P Ernst et al.

    Relative scarcity of asthma and atopy among rural adolescents raised on a farm

    Am J Respir Crit Care Med.

    (2000)
  • J Riedler et al.

    Austrian children living on a farm have less hay fever, asthma and allergic sensitization

    Clin Exp Allergy.

    (2000)
  • E von Mutius et al.

    Exposure to endotoxin or other bacterial components might protect against the development of atopy

    Clin Exp Allergy.

    (2000)
  • W Eduard et al.

    Do farming exposures cause or prevent asthma? results from a study of adult Norwegian farmers

    Thorax.

    (2004)
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    This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases (R01AI61774, R01AI50681) and the Fund for Henry Ford Hospital.

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