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.

特应性体质在出生后不久就开始出现特应性皮炎（AD）和食物致敏， 临床食物过敏（FA）潜在发展的重要标志物。农耕生活方式 与学龄期哮喘和特应性疾病风险降低相关。持续微生物 建议在农场生活时经历的暴露通过引发先天免疫来提供保护。 细胞群/受体，而增加单核细胞活化和高反应性细胞因子反应， 脂多糖（LPS）刺激与过敏性哮喘的风险增加有关。后生 骨髓细胞的修饰可以导致对第二种刺激的功能潜力发生变化，无论是 增强或抑制反应。这种免疫潜力的长期修饰，一个被称为训练的概念， 免疫，可以导致一系列功能结果，类似于T细胞分化结果， 影响力的社会还提出通过调节性T（Treg）细胞的扩增来介导农场生命保护。 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 一代的Tibet。这可以通过维持上皮屏障完整性来增强耐受性， 已知在AD的皮肤中受损，促进表皮过敏原致敏和胃肠道过敏原致敏。 在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尚不清楚。 虽然新出现的预防战略要求必须查明那些处于危险之中的人，但这些人的特点仍然很突出。 我们在“放大到旧秩序门诺派”（ZOOM）1出生队列中的初步研究发现， 婴儿期记忆效应细胞Th 2亚群作为婴儿变应性致敏发展的标志 出生于罗切斯特的城市家庭（ROC）。相比之下，我们的研究发现， 在来自旧秩序的婴儿中表达TIGIT（一种抑制性共刺激分子）的（β7+）TcR和TcR 门诺派教徒（OOM），一个传统的农业社区，防止过敏性疾病。此外，ROC婴儿 在脐带血中表现出高度炎症性单核细胞反应。利用样本和临床数据 在已入组ZOOM 1队列（n=160）和待入组扩展队列ZOOM 2中收集 （n=120），我们将测试我们的中心假设，即婴儿谁将发展特应性疾病产生Th 2- 在婴儿早期，T细胞群倾斜，而受保护的婴儿发展肠道归巢抑制性T细胞， 以及单核细胞对LPS和病毒靶点低反应。我们有三个具体目标：目标1将评估 农业和城市生活方式中与保护相关的婴儿适应性和先天免疫标记 和特应性疾病的结果。目的2将评估T细胞和先天细胞转录组的作用， 表观基因组对特应性疾病结局的影响目标3将测量肠道屏障与 功能，农业生活方式和特应性疾病。在完成这项工作后，我们预计将确定 与抗过敏免疫相关的机制和生物标志物。