Project 1: Immune development and respiratory outcomes in children from diverse Wisconsin communities

项目总结 早期生命的免疫系统需要“训练”来降低对传染病的脆弱性，这是时候了 非传染性、免疫介导性疾病，如过敏性疾病， 都是成立的。早年暴露在农业环境中已被证明具有保护作用 对抗过敏性疾病的发展。我们已经成功地建立了一个新的出生队列 威斯康星州婴儿研究队列(WISC)。WISC是一个美国农村出生的队列，婴儿来自奶牛场，农村，非 农业环境，以及来自阿米什社区的婴儿，他们拥有非常传统的土地(TA)生活方式。 我们的研究结果显示，特应性皮炎的发生率降低，病毒性呼吸道疾病减少 暴露于农场的婴儿出生后第一年内脂多糖诱导的单核细胞细胞因子产生的频率和增加 婴儿。我们的初步数据显示，TA儿童的过敏性疾病发生率非常低，独特的肠道和 与农场和非农场相比，鼻部微生物区系、先天成熟和免疫调节标志物增加 2岁以下的农场儿童。关于是否以及如何解决仍有一些重要的问题 先天免疫细胞能力和免疫调节功能在生命早期与疾病风险有关。 这项提案的一个主要目标是定义免疫和环境特征，以防止过敏 和病毒性呼吸道疾病在农场暴露的儿童，并确定免疫，鼻腔 上皮谱和微生物组。我们的中心假设是与农场相关的微生物定植 促进不同免疫表型和鼻腔上皮表型的发展，部分是通过 表观遗传改变，降低过敏性致敏风险，增加粘膜抗病毒反应。 我们假设阿米什人将有不同的免疫特征和微生物暴露，农场参与者将 作为中介机构和非农业机构，被认为是风险相对较高的研究群体。为了解决这一假设，我们将 继续WISC+直到5岁，并建立一个新的横断面队列。我们的研究包括三个部分 瞄准并利用尖端技术，利用我们在农场分娩方面的丰富经验 队列和学习团队的专业知识。目的1.表征纵向表型和表观遗传轨迹 TA、农场和非农场儿童的单核细胞和调节性免疫细胞从5岁一直到5岁。目标2.目标 确定TA与农场暴露、鼻呼吸道上皮细胞基因表达和 对自然发生的病毒性呼吸道疾病的反应。我们将进行一个观察性的、横断面的、案例- 三组学龄儿童对照队列研究(称为微生物相关性呼吸系统疾病，MARI) 儿童(100人/组)：TA儿童、无哮喘的郊区儿童和有哮喘的郊区儿童 检查鼻黏膜生理学和病毒性呼吸道疾病。目的3.找出鼻腔呼吸道的差异 TA儿童、无哮喘的郊区儿童和患有哮喘的郊区儿童的上皮细胞dNaM模式 与自然发生的呼吸道疾病的频率和严重程度有关的哮喘。

PROJECT SUMMARY The early life immune system requires “training” to decrease vulnerability to infectious diseases and is the time period when risks for development of non-communicable, immune-mediated diseases, such as allergic diseases, are established. Early life exposure to the farming environment has been shown to provide a protective role against the development of allergic diseases. We have successfully established a novel birth cohort called Wisconsin Infant Study Cohort (WISC). WISC is a rural US birth cohort with infants from dairy farms, rural, non- farming environments, and infants from Amish communities who have a very Traditional Agrarian (TA) lifestyle. Our study findings demonstrate decreased incidence of atopic dermatitis, decreased viral respiratory illness frequency and increased LPS-induced monocyte cytokine production during the first year of life in farm-exposed infants. Our preliminary data demonstrate TA children have very low rates of allergic disease, unique gut and nasal microbiota, and increased innate maturation and immune regulatory markers compared to farm and non- farm children through age 2 years. There remain unresolved and important questions as to whether and how innate immune cell competence and immunoregulatory function are related in early life and their risk for disease. A major goal of this proposal is to define the immune and environmental signatures for protection from allergic and viral respiratory diseases in farm exposed children and determine the relationship between immune, nasal epithelial profiles and microbiome. Our central hypothesis is that farm-related microbial colonization promotes the development of distinct immune and nasal epithelial phenotypes mediated, in part, through epigenetic changes that reduce risk for allergic sensitization and increase mucosal antiviral responses. We hypothesize the Amish will have distinct immune profiles and microbial exposures, the farm participants will be intermediaries, and non-farm considered a relatively at-risk study group. To address this hypothesis, we will continue WISC+ through age 5 years and establish a new cross-sectional cohort. Our study consists of three aims and makes use of cutting-edge technologies that leverages our extensive experience with farm-related birth cohorts and study team expertise. Aim 1. To characterize the longitudinal phenotypes and epigenetic trajectory of monocyte and regulatory immune cells of the TA, farm and non-farm children through age 5 years. Aim 2. To determine the relationship between TA and farm exposures, nasal airway epithelial cell gene expression and response to naturally occurring viral respiratory illness. We will conduct an observational, cross-sectional, case- control cohort study (called Microbial Associated Respiratory Illnesses, MARI) of three groups of school-age children (100/group): TA children, suburban children without asthma, and suburban children with asthma to examine nasal mucosal physiology, and viral respiratory illnesses. Aim 3. To identify differences in nasal airway epithelial cell DNAm patterns in TA children, suburban children without asthma, and suburban children with asthma that are associated with the frequency and severity of naturally occurring respiratory illnesses.