Mechanism of Endotoxin's Effect On Allergy Risk

描述（由申请人提供）：许多研究表明，早期暴露于内毒素与哮喘和过敏的风险较低相关。本研究的总体目标是了解这种影响的机制。这包括1）阐明内毒素是否通过Toll样受体（TLR）的结合和活化介导其作用，和2）确定内毒素在T细胞分化中的作用。已知Toll样受体（TLR）-2、TLR-4和CD 14结合内毒素并介导其对先天免疫系统的刺激。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（Th 2）似乎负责过敏性表达，内毒素可能的下游效应是抑制这种T细胞表型。由于TLR家族识别广泛的感染性生物体，因此澄清这种机制对长期存在但未经证实的“卫生假说”具有明显的意义，该假说假定早期感染和过敏性发展之间存在保护性关联。这里提出的研究将利用2003年9月在底特律地区开始的一个大型的、前瞻性的、多种族的出生队列。为了实现第一个目标，将在出生后第一年在家中测量内毒素水平，并将其与随后的血清学和皮肤点刺特应性测量相关。将研究已知引起CD 14、TLR-2和TLR-4表达或功能改变的单核苷酸多态性（SNP）。如果TLR通路介导内毒素对过敏的影响，那么具有这些多态性的儿童应该表现出对内毒素的反应改变或减弱。第二个目的是确定内毒素暴露是否导致辅助性T细胞表型的偏斜（即，Thl对Th 2）或是否导致T细胞无反应性。为了实现这一目标，将前瞻性测量CD 4+淋巴细胞中的细胞内细胞因子产生。将在6个月、1岁和2岁时测量脐带血中的白细胞介素（IL）-4，IL-10和干扰素-3。由于CD 4 +/CD 25+调节性T细胞似乎是无反应性的原因，这组细胞随时间的变化将与内毒素暴露水平相关。人们希望了解内毒素的作用机制将为预防过敏建立新的靶点。

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.