Innate and Adaptive Immune Markers in Farming Lifestyle and Early Atopic Diseases

特应性体质在出生后不久就开始出现，患有特应性皮炎(AD)和对食物的过敏，这是一种 临床食物过敏(FA)潜在发展的重要标志物。一种农业生活方式一直是 可重复地与学龄期哮喘和特应性疾病的风险降低相关。持续微生物 在农场生活时所经历的暴露建议通过启动先天免疫来提供保护 群体/受体，而单核细胞活化和高反应性细胞因子反应增加 脂多糖(LPS)刺激与过敏性哮喘风险增加相关。表观遗传 髓系细胞的修饰可以导致对第二种刺激的功能潜力的改变，无论是 增强的或抑制的反应。这种对免疫潜力的长期修饰，这个概念被称为训练 免疫，可以导致一系列的功能结果，类似于他们的T细胞分化结果 影响力。农场生活保护也被认为是通过扩增调节性T(Treg)细胞来调节的。 通过表观遗传机制或与免疫细胞的直接相互作用，微生物代谢产物促进 一代特雷格人。这可以通过维持上皮屏障的完整性来加强耐受性，这是 已知在AD患者的皮肤中受到损害，促进皮肤表面性过敏原敏化和胃肠道 位于FA的站点。尽管有几个大的出生队列，但AD和FA的早期机制和生物标志物很差 尽管新出现的预防战略要求需要确定那些处于危险之中的人，但这是一个具有鲜明特点的问题。 我们在《放大到旧秩序门诺派》(ZOOM)1部出生队列小说中的初步研究 婴儿期记忆效应器Th2亚群作为婴幼儿变态反应敏化发展的标志 出生于罗切斯特城市家庭(中华民国)。相比之下，我们的研究发现，肠道归宿的频率更高 (β7+)表达抑制性共刺激分子TIGIT的树突状细胞和旧目婴儿的树突状细胞 门诺派(OOM)，一个传统的农业社区，防止特应性疾病。此外，中华民国婴儿 在脐带血中显示出高炎性单核细胞反应。利用样本和临床数据 在已登记的ZOOM1队列(n=160)下收集，并待登记的扩展队列ZOOM 2 (n=120)，我们将检验我们的中心假设，即患有特应性疾病的婴儿会产生Th2- 在婴儿早期，扭曲的T细胞群，而受保护的婴儿发展肠道归巢抑制性树， 单核细胞对内毒素和病毒靶标反应迟钝。我们有三个具体目标：目标1将评估 与保护相关的农业和城市生活方式中的婴儿适应性和先天免疫标志物 和特应性疾病的结果。目的2将评估T和固有细胞转录组和 关于特应性疾病结局的表观基因组。目标3将测量肠道屏障之间的联系 功能、耕作方式和特应性疾病。在这项工作完成后，我们预计将确定 与抗过敏免疫相关的机制和生物标志物。

Atopic constitution starts shortly after birth with atopic dermatitis (AD) and sensitization to foods, which is an important marker for the potential development of clinical food allergy (FA). A farming lifestyle has been reproducibly associated with a reduced risk of asthma and atopic disease at school-age. Sustained microbial exposure experienced when living on farms is proposed to confer protection through priming of innate immune populations/receptors, whereas increased monocyte activation and hyper-responsive cytokine response to lipopolysaccharide (LPS) stimulation was associated with increased risk of allergic asthma. Epigenetic modifications in myeloid cells can lead to a change in functional potential to a second stimulus, either an enhanced or suppressed response. This long-lived modification in immune potential, a concept known as trained immunity, can lead to an array of functional outcomes, similar to the T cell differentiation outcomes that they influence. Farmlife protection is also proposed to be mediated through expansion of regulatory T (Treg) cells. Through epigenetic mechanisms or direct interaction with immune cells, microbial metabolites promote generation of Tregs. This can reinforce tolerance through maintenance of epithelial barrier integrity, which is known to be compromised in skin in AD, facilitating epicutaneous allergen sensitization and in gastrointestinal sites in FA. Despite several large birth cohorts, the early mechanisms and biomarkers of AD and FA are poorly characterized, although the emerging strategies for prevention call for a need to identify those at risk. Our preliminary studies in the “Zooming in to Old Order Mennonites” (ZOOM)1 birth cohort identified novel memory effector Th2 subpopulations in infancy as a marker of development of allergic sensitization in infants born to Rochester urban families (ROC). In comparison, our studies found a higher frequency of gut-homing (β7+) Tregs and Tregs that express TIGIT, an inhibitory co-stimulatory molecule, in infants from Old Order Mennonites (OOM), a traditional agrarian community protected against atopic diseases. In addition, ROC infants demonstrated a hyper-inflammatory monocyte response in cord blood. Utilizing samples and clinical data collected under the already enrolled ZOOM1 cohort (n=160) and to be enrolled expansion cohort ZOOM 2 (n=120), we will be testing our central hypothesis that infants who will develop atopic diseases generate Th2- skewed T cell populations in early infancy, whereas the protected infants develop gut-homing suppressive Tregs, and monocytes hyporesponsive to LPS and viral targets. We have three specific aims: Aim 1 will assess infant adaptive and innate immune markers in farming and urban lifestyles associated with protection and atopic disease outcomes. Aim 2 will evaluate the role of T and innate cell transcriptome and epigenome on atopic disease outcomes. Aim 3 will measure the association between gut barrier function, farming lifestyle, and atopic diseases. Upon completion of this work, we expect to identify mechanisms and biomarkers associated with anti-allergic immunity.