A number of studies suggest that early exposure to endotoxin is associated with a lower risk of asthma and allergies. The overall objective of this research is to understand the mechanism of that effect. This includes 1) clarifying whether endotoxin mediates its effect through the binding and activation of Toll-like receptors (TLRs), and 2) determining endotoxin's role in T-cell differentiation. Toll-like receptor (TLR)-2, TLR-4, and CD 14 are known to bind endotoxin and to mediate its stimulation of the innate immune system. What is not known is whether this pathway also mediates endotoxin's effect on allergy. As type-2 helper T-cells (Th2) appear to be responsible for allergic expression, endotoxin's probable downstream effect is suppression of this T-cell phenotype. Since the TLR family recognizes a broad range of infectious organisms, clarifying this mechanism has obvious implications for long-standing, but unproven, """"""""Hygiene Hypothesis,"""""""" which posits a protective association between early infections and allergic development. The research proposed here will take advantage of a large, prospective, multi-ethnic, birth cohort which began in the Detroit area in September 2003. To achieve the first objective, endotoxin levels will be measured in the home in the first year of life and related to subsequent serologic and skin prick measures of atopy. Single nucleotide polymorphisms (SNPs) known to cause alterations in either the expression or the function of CD14, TLR-2, and TLR-4 will be studied. If the TLR pathway mediates endotoxin's effect on allergy, children with these polymorphisms should display an altered or diminished response to endotoxin. The second objective will determine whether endotoxin exposure results in skewing of the helper T-cell phenotype (i.e., Thl vs. Th2) or whether it results in T-cell anergy. To achieve this objective, intracellular cytokine production in CD4+ lymphocytes will be prospectively measured. Interleukin (IL)-4, IL-10, and interferon-3, will be measured in cord blood, at 6 months, 1 year, and 2 years of age. As CD4+/CD25+ regulatory T-cells appear to be responsible for anergy, changes in this group of cells over time will be related to the level of endotoxin exposure. It is the hoped that understanding the mechanism of endotoxin's effect will establish new targets for the prevention of allergies.
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