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

农业生活方式和早期特应性疾病中的先天性和适应性免疫标志物

• 批准号: 10633369
• 负责人: Kirsi Jarvinen-Seppo
• 金额: $ 43.89万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633369
• 关键词: ATAC-seq; Allergens; Allergic; Allergic Disease; Anti-Allergic Agents; Asthma; Atopic Dermatitis; Bifidobacterium; Biological Markers; Birth; Blood; Cells; Clinical Data; Communities; Constitution; Constitutional; Development; Disease; Disease Outcome; Enrollment; Epigenetic Process; Epithelial Cells; Epithelium; Extrinsic asthma; Family; Farm; Feces; Flow Cytometry; Food; Food Hypersensitivity; Frequencies; Gene Expression; Generations; Genetic Transcription; Goals; Homing; IgE; Immune; Immunity; Immunologic Markers; Immunophenotyping; In Vitro; Individual; Infant; Inflammatory; Intervention; Intestinal permeability; KLRB1 gene; Life Style; Lipopolysaccharides; Maintenance; Measures; Mediating; Memory; Mennonite; Modification; Myeloid Cells; Outcome; Pathogenicity; Permeability; Phenotype; Population; Prevention strategy; Proliferating; Regulatory T-Lymphocyte; Reproducibility; Risk; Role; Sampling; School-Age Population; Signal Transduction; Site; Skin; Sterility; Stimulus; T cell differentiation; T-Lymphocyte; TLR4 gene; Testing; Training; Umbilical Cord Blood; Viral; Water; Work; atopy; clinical development; cohort; cytokine; early detection biomarkers; epigenome; experience; food antigen; functional outcomes; gastrointestinal; gastrointestinal epithelium; gut microbiome; high risk; in vivo; infancy; infant gut microbiome; intestinal barrier; intestinal epithelium; microbial; monocyte; novel; receptor; response; single-cell RNA sequencing; transcriptome

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.

特应特应性皮炎（AD）出生后不久开始，并且对食物的敏感性 临床食品过敏（FA）潜在发展的重要标志。农业生活方式已经 可重复与学龄时哮喘和特应性疾病的风险降低有关。持续微生物 建议生活在农场时经历的暴露是通过启动先天免疫来提供保护的 种群/受体，而单核细胞激活增加和对细胞因子对 脂多糖（LPS）模拟与过敏性哮喘的风险增加有关。表观遗传学 在 增强或抑制的响应。这种长期的免疫潜力修改，一个被称为训练的概念 免疫力，可以导致一系列功能结果，类似于它们的T细胞分化结果 影响。还建议通过扩展调节t（Treg）细胞来介导农业生物保护。 通过表观遗传机制或与免疫细胞直接相互作用，微生物代谢物促进 产生Tregs。这可以通过维持上皮屏障完整性来增强耐受性，即 已知在AD中受到皮肤的损害，支持表皮过敏原感应和胃肠道 FA的网站。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还是很差的 表征，尽管预防的新兴策略要求确定有风险的人。 我们在“缩放到旧顺序的门诺派”（Zoom）1生日队列中的初步研究确定了小说 记忆效应子Th2在婴儿期的亚群，作为婴儿过敏性感觉发展的标志 罗切斯特城市家庭（ROC）出生。相比之下，我们的研究发现肠道的频率更高 （β7+）表达tigit的treg和tregs，一种抑制性共刺激分子，来自旧顺序的婴儿 Mennonites（OOM），一个传统的农业社区，免受特应疾病的保护。另外，ROC婴儿 在脐带血中证明了过度炎症的单核细胞反应。利用样品和临床数据 在已经注册的Zoom1队列（n = 160）下收集，并招募扩展队列Zoom 2 （n = 120），我们将测试我们的中心假设，即会产生特应性疾病的婴儿会产生Th2- 偏斜的T细胞群体在婴儿早期期，而受保护的婴儿会出现肠道抑制性的Treg， 和单核细胞对LP和病毒靶标的反应。我们有三个具体的目标：AIM 1将评估 婴儿适应性和先天免疫标记在农业和城市生活方式中与保护相关 和特应性疾病的结果。 AIM 2将评估T和先天细胞转录组的作用以及 特应性疾病结局的表观基因组。 AIM 3将衡量肠道障碍之间的关联 功能，农业生活方式和特应性疾病。完成这项工作后，我们希望确定 与抗过敏性免疫相关的机制和生物标志物。