Mechanism of Endotoxin's Effect On Allergy Risk

描述(由申请人提供)：许多研究表明，早期接触内毒素与哮喘和过敏的风险较低有关。本研究的总体目标是了解这一效应的机制。这包括1)阐明内毒素是否通过结合和激活Toll样受体(TLRs)来介导其作用，以及2)确定内毒素在T细胞分化中的作用。Toll样受体(TLR)-2、TLR-4和CD14可与内毒素结合并介导其对天然免疫系统的刺激作用。目前尚不清楚的是，这一途径是否也介导了内毒素对过敏的影响。由于2型辅助性T细胞(Th2)似乎与过敏表达有关，内毒素可能的下游作用是抑制这种T细胞表型。由于TLR家族识别广泛的感染性生物，澄清这一机制对长期存在但未经证实的“卫生学假说”具有明显的影响，该假说假设在早期感染和过敏发生之间存在保护性联系。这里提出的这项研究将利用2003年9月在底特律地区开始的一个大型、预期的、多种族的出生队列。为了实现第一个目标，将在生命的第一年在家中测量内毒素水平，并与随后的血清学和皮肤刺激性特应性措施相关。已知引起CD14、TLR-2和TLR-4表达或功能改变的单核苷酸多态(SNPs)将被研究。如果TLR途径介导了内毒素对过敏的影响，具有这些基因多态性的儿童应该对内毒素表现出一种改变或减弱的反应。第二个目标将确定内毒素暴露是否导致辅助性T细胞表型倾斜(即Th1与Th2)或是否导致T细胞无能。为了实现这一目标，将前瞻性地测量CD4+淋巴细胞细胞内细胞因子的产生。将在6个月、1岁和2岁时检测脐带血中的IL-4、IL-10和干扰素-3。由于CD4+/CD25+调节性T细胞似乎与无能有关，随着时间的推移，这组细胞的变化将与内毒素暴露的水平有关。希望通过对内毒素作用机制的深入研究，为过敏的预防提供新的靶点。

DESCRIPTION (provided by applicant): 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.