Mechanisms of DiseaseRole of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults
Introduction
The hygiene hypothesis suggests that decreasing exposure to infections or bacterial products is the cause of the increasing incidence of atopy and asthma.1, 2, 3 Epidemiological studies have consistently shown that the farming environment is protective in young children against development of hayfever, atopy, and wheeze. Bacterial lipopolysaccharide has been suggested as a potential mediator of these protective effects.4, 5, 6, 7 Although epidemiological evidence supports the role of bacterial lipopolysaccharide in the hygiene hypothesis, the mechanisms of any lipopolysaccharide-induced immunomod-ulation or modification of an allergic immune response during early life are poorly understood.
We have shown previously that although exposure of rats to lipopolysaccharide during early sensitisation protects against their development of ovalbumin-specific IgE,8 coexposure of lipopolysaccharide with allergen results in dose-dependent inhibition of acute and late-phase allergic inflammation and bronchial hyper-responsiveness;9 exposure to lipopolysaccharide after allergen challenge further exacerbates the allergic response.8 The effect of lipopolysaccharide depended on the timing of exposure and the dose given. We have shown lately that administration of lipopolysaccharide to explanted nasal mucosa of young non-atopic children shifts the immune response towards a T-helper 1 (Th1) phenotype by causing inflammatory cell activation and promoting strong proliferation of T cells.10 This model shows many of the features of in-vivo lipopolysaccharide-induced inflammation previously described in both animals and human beings, including cellular activation, production of cytokines, and mast-cell degranulation. Importantly, these effects of lipopolysaccharide were mediated locally without recruitment of inflammatory cells from the systemic circulation.
To investigate further the effect of lipopolysaccharide on allergic inflammation in the nasal mucosa of young atopic children, we used the above explant model to compare the responses with those in atopic adults. We decided to stimulate the allergic mucosa simultaneously with allergen and lipopolysaccharide to mimic the normal environmental exposure more closely, because both of these antigens are ubiquitous contaminants in the environment. We hypothesised that lipopolysaccharide can downregulate the allergen-induced local inflammation in the nasal mucosa of atopic children by causing a shift from a Th2 towards a Th1 immune response and inducing production of the immunoregulatory cytokine interleukin 10.
Section snippets
Participants
22 children and 17 adults were recruited for this study. 15 atopic children (mean age 3·2 years [SD 0·4]) and seven non-atopic children (mean age 3·8 years [0·7]) of both sexes were recruited from the ear, nose, and throat clinic at the Montreal Children's Hospital. Atopy was confirmed by skin-prick testing to a panel of common allergens including housedust mite, grass pollen, ragweed extract, and cat and dog antigens. Non-atopic children had no history of asthma or other allergic diseases and
Results
In non-stimulated atopic mucosa of children, we detected constitutively expressed CD68, major basic protein, elastase, tryptase, CD3, interleukin 2, and CD25. Similarly, constitutive expression of mRNA for both Th2 (interleukins 4, 5, 13, and 10) and Th1 (interferon γ, interleukin 12) cytokines was detected in this tissue.
Exposure of atopic mucosa to lipopolysaccharide without allergen significantly increased the number of cells immunoreactive for CD68 (p=0·0009), elastase (p=0·01), tryptase
Discussion
We have extended our previous studies with an ex-vivo human model of lipopolysaccharide-induced inflammation in explanted nasal mucosa from non-atopic children to show that administration of lipopolysaccharide can skew the local allergic response in young atopic children away from a Th2 towards a Thl immune response. The shift in cytokine profile is associated with increased production of immunoregulatory interleukin 10, proliferation of CD3-positive T lymphocytes and increased numbers of
GLOSSARY
- cytokines
- A family of small, low-molecular-weight proteins involved in intercellular signalling, growth, proliferation, and cell death.
- hygiene hypothesis
- The idea that low exposure to bacterial products, especially during early life, might be the reason for the increasing incidence of asthma.
- lipopolysaccharide
- A major component of the cell wall of gram-negative bacteria.
- toll-like receptor 4
- A receptor involved in lipopolysaccharide-induced signal transduction.
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