Pierre-Olivier Fiset

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

BACKGROUND Exposure to bacterial products in early life could protect against development of atopy. We examined the effect of bacterial lipopolysaccharide on allergic inflammation and expression of cytokines and lipopolysaccharide receptor (toll-like receptor 4 TLR4) in nasal mucosa of 15 atopic children and ten atopic adults. METHODS Explanted mucosa was cultured with allergen with or without lipopolysaccharide (0.1 mg/L) for 24 h. Immunocytochemistry and in-situ hybridisation were used to phenotype the cells and cytokines. FINDINGS In explants from atopic children, lipopolysaccharide prevented allergen-induced T-helper type 2 (Th2) inflammation and upregulated Th1 cytokine reactivity and expression. These effects were blocked by antibody to interleukin 10. In children but not in adults, lipopolysaccharide caused increases of three times in T-cell reactivity, five times in T-cell proliferation, and four times in expression of interleukin 10 compared with mucosa stimulated with allergen alone. This difference in response was mirrored by lipopolysaccharide-induced increases in TLR4 reactivity in children but not adults. TLR4 receptor was expressed by CD3-positive T cells, and TLR4-positive cells contained interleukin 10. Lipopolysaccharide increased expression of cells positive for both CD3 and TLR4; both TLR4 and interleukin 10; and both CD4 and CD25. INTERPRETATION Lipopolysaccharide inhibits allergic inflammation in nasal mucosa of atopic children by skewing local immune responses from Th2 to Th1 and upregulating production of interleukin 10. These effects are mediated by TLR4. Our results emphasise an important difference between adults and children in their ability to respond to bacterial products. These differences could have a role in normal maturation of the immune system.

Children with atopic histories exhibit impaired lipopolysaccharide-induced Toll-like receptor-4 signalling in peripheral monocytes

Background The hygiene hypothesis states that early exposure to bacterial products such as lipopolysaccharide (LPS) may be protective against the development of allergic diseases. Whether atopic disease affects the ability of immune cells to respond to LPS is unclear. Our laboratory has demonstrated previously that children express high levels of Toll‐like receptor (TLR)‐4 on CD4+ cells in nasal mucosa.

Signal transducer and activator of transcription 6 down‐regulates toll‐like receptor‐4 expression of a monocytic cell line

Background Toll‐like receptor 4 (TLR4), part of the bacterial lipopolysaccharide (LPS) receptor, is an important bridge between innate and adaptive immunity. Our previous studies have indicated reduced expression of TLR4 and reduced responsiveness to LPS in nasal mucosa of atopic adults compared with non‐atopic adults. IL‐4 and signal transducer and activator of transcription 6 (STAT6), which are increased in atopic patients, may have a role in modulating TLR4.

Atopy affects LPS responsiveness and TLR-4 expression in children peripheral mononuclear cells

Background Lipopolysaccharide (LPS) exposure in early life is associated with a lower incidence of atopy. We sought to determine whether atopy regulates TLR-4 expression and LPS-induced signal transduction on peripheral immune cells e.g. CD4 T ‘helper’ T cells, monocytes and B cells of a large pediatric cohort.