Human Immunotoxicity of Developmental PCB Exposure

新出现的实验和观察数据表明，免疫系统很容易受到这种影响。 早期生命暴露于外源因素的可能性。免疫系统在子宫内开始发育，并继续 在青春期和成年期早期经历严格控制的发育过程。然而， 关于生命早期环境暴露如何改变免疫易感性的知识仍然很少 在整个儿童期和青春期，尤其是对人类免疫系统来说，细胞的功能缺陷是最重要的。 目前的证据表明，环境暴露扰乱了早期生命中的人类免疫功能 仅限于婴幼儿。目前，几乎没有关于这些观察到的信息 与其他关键发育阶段的免疫功能有关，如青春期。这样做的目的是 项目是定义如何接触到特定类别的环境制剂，多氯联苯 (多氯联苯)，在关键的发育期，影响免疫功能，从童年到 青春期。这项拟议的工作直接建立在婴儿体内较高的多氯联苯水平与 在斯洛伐克东部的一个出生队列中，疫苗应答率较低，呼吸道发病率较高。这个 拟议的工作将检查这一队列中400名青少年的适应性免疫功能和感染情况。建房 我们发现，6个月的多氯联苯水平与抗卡介苗特异性抗体水平呈负相关，我们的 第一个目标是在45个月、7岁和16岁时测定免疫球蛋白和免疫球蛋白A特异性的抗BCG和-MMR水平 年龄。利用广泛的出生前和出生后暴露数据，这将允许估计特定年龄的多氯联苯- 抗体关联，以及允许随着时间的推移估计疫苗反应轨迹。这个目标是 尤其重要的是，因为在婴儿时期接种疫苗的目的是创造持久的反应， 随着儿童年龄的增长，有助于保护儿童。我们的第二个目标是检查与功能相关的电路板暴露 不同的B细胞和T细胞亚群。较高的多氯联苯浓度与较低的抗体水平有关 在几项研究中进行了疫苗接种。然而，其机制尚不清楚，特定的淋巴细胞亚型和 功能能力的特点仍然很差：来自这一目标的数据将有助于填补这一知识缺口。在第三节 目的：我们将使用基于聚合酶链式反应的方法来测量22种常见呼吸道病原体在1- 一年的随访期，包括无症状和有症状的收集。我们还将抽象医生- 从出生到16岁被诊断为下呼吸道感染(LRTI)。有了这些测量的端点， 出生前后多氯联苯浓度与有症状和无症状呼吸的关系 将对感染情况进行评估。通过将这一既定队列的研究从出生扩展到青春期，我们将 获取有关这类常见污染物如何影响人类免疫系统的新信息。

Emerging experimental and observational data suggest that the immune system is susceptible to the influence of early life exposure to exogenous factors. The immune system begins to develop in utero, and continues to undergo tightly regulated developmental processes through adolescence and early adulthood. However, knowledge remains scant regarding how environmental exposures earlier in life modify susceptibility of immune cells to functional deficits throughout childhood and into adolescence, especially for the human immune system. Current evidence that environmental exposures perturb human immune function during early life is primarily limited to infants and young children. Presently, there is almost no information about how these observations relate to immune function during other critical developmental stages, such as adolescence. The objective of this project is to define how exposure to a specific category of environmental agents, polychlorinated biphenyls (PCBs), during key developmental periods, affects immune functions throughout childhood and into adolescence. The proposed work builds directly on findings that higher infant PCB levels are strongly associated with lower vaccine responses and greater respiratory morbidity in a birth cohort in eastern Slovakia. The proposed work will examine adaptive immune function and infection in 400 adolescents from this cohort. Building on our finding that 6-month PCB levels were inversely associated with anti-BCG specific antibody levels, our first aim will determine IgG- and IgA-specific anti-BCG and -MMR levels at 45 months, and 7 and 16 years of age. Leveraging extensive pre- and postnatal exposure data, this will allow the estimation of age-specific PCB- antibody associations, as well as permit the estimation of vaccine response trajectory over time. This aim is particularly important since vaccines administered in infancy are intended to create durable responses that contribute to protection as children age. Our second aim examines PCB exposure in relation to functionality of distinct B cell and T cell subsets. Higher PCB concentrations are associated with lower antibody levels to vaccination in several studies. However, the mechanism is not known, and specific lymphocyte sub-types and functional capacity remain poorly characterized: data from this aim will help fill this knowledge gap. In the third aim, we will use PCR-based methods to measure the frequency of 22 common respiratory pathogens over a 1- year period of follow-up, including asymptomatic and symptomatic collections. We will also abstract physician- diagnosed lower respiratory tract infections (LRTIs) from birth through 16 years. With these measured endpoints, associations between pre- and postnatal PCB concentrations and symptomatic and asymptomatic respiratory infection will be assessed. By extending research with this established cohort from birth to adolescence, we will obtain new information about how this category of common pollutants impacts the human immune system.