Development of Mucosal and Systemic Immunity and Risk of Food Allergy

粘膜和系统免疫的发展以及食物过敏的风险

基本信息

批准号：
9895622
负责人：
Kirsi Jarvinen-Seppo
金额：
$ 44.94万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895622
关键词：
16S ribosomal RNA sequencing Age-Months Allergens Allergic Allergic Disease Allergy to peanuts Animal Model Animals Antibiotics Antibodies Antibody Response Autoimmune Diseases B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Bacteria Biological Markers Birth Cattle Child Childhood Childhood Asthma Clinical Clinical Trials Cohort Studies Consumption Data Defect Developed Countries Development Diet Disease Eczema Environment Environmental Risk Factor Exhibits Exposure to Extrinsic asthma Family Farming environment Feces Flow Cytometry Food Food Hypersensitivity Future Genomics Germ-Free Home environment Hypersensitivity IgE Immune Immune response Immune system Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Variable Region Immunoglobulins Immunology Infant Infant Development Intervention Knowledge Learning Life Life Style Measures Memory B-Lymphocyte Mennonite Milk Mucosal Immunity Mucous Membrane Neonatal Oral Outcome Plasma Cells Play Population Predisposition Prevention Research Risk Role Saliva Secretory Immunoglobulin A Serum Somatic Mutation Sorting - Cell Movement Systems Development T-Lymphocyte Training Transcript Umbilical Cord Blood Vaginal delivery procedure animal data atopy base cohort design early onset food allergen gut microbiome gut microbiota high risk high risk population immunogenic immunogenicity infancy microbial microbiome microorganism antigen mucosal site neonate peripheral blood postnatal prevent response support vector machine

项目摘要

The microbiome plays a critical role in the development of the immune system and alterations in the microbiome diversity almost certainly play an important role in the surge of allergic and autoimmune diseases in developed nations that began in the 1950's and continues today. Living on farms, avoiding antibiotics, vaginal delivery, and other environmental factors leading to greater diversity in the microbiome have been associated with a major reduction in the risk of atopic diseases. Understanding the development of the immune system in populations at low risk for allergy compared to high-risk populations, developing biomarkers for “protective” immune development, and assessing immune responses to the microbiome are fundamental for designing and assessing future interventions. In this proposal, we will compare the Old Order Mennonites (OOM) with a very low risk for food allergies (<1%), other allergic diseases and asthma and a lifestyle associated with a diverse microbiome (e.g. growing up on a farm, consumption of raw milk, large families, home deliveries, low rate of antibiotic use), and neonates born to families with food-allergic children with a very high risk for developing atopic diseases, e.g. a 15-20% risk of food allergy in the first year of life. We hypothesize that accelerated development of IgA mucosal immunity will be a biomarker for “protective” immune development. Abundant IgA-coated fecal bacteria are seen in early life and data from animal models indicate the importance of microbial diversity in the induction of this secretory IgA. Early studies suggest that the predisposition to the development of IgE antibodies (“atopy”) is associated with a slow development of IgA responses, e.g. our own data shows a delay in development of specific IgA in cow's milk-allergic infants. Exciting new discoveries further support the role for specific IgA come from trials of orally induced tolerance in established food allergy. Because there is an intimate reciprocal development of gut microbial communities with the IgA repertoire, we hypothesize that mucosal exposure to a diverse and immunogenic microbiome accelerates the development of IgA secretory immunity, counteracts development of IgE responses, and protects from allergic diseases. We will assess how B cell subsets, immunoglobulin repertoire and somatic mutation rates (Aim 1), and gut microbiome and IgA antibody responses to microbiome develop in cohorts of high- and low-risk for allergy (Aim 2), and how these B cell biomarkers and gut microbiome relate to the development of food and other allergic diseases and humoral responses to allergens (Aim 3). In summary, this proposal will determine whether accelerated development of IgA responses is a biomarker for “protective” immune development, identify fecal bacteria inducing IgA responses, and assess the association of specific IgA immune responses with clinical tolerance, i.e. protection from early-onset food allergy and eczema.

微生物组在免疫系统的发育和免疫系统的改变中起着至关重要的作用微生物组多样性几乎肯定在过敏性和自身免疫性疾病的激增中发挥着重要作用在发达国家，这种做法始于 20 世纪 50 年代，一直延续到今天。生活在农场，避免使用抗生素，阴道分娩和其他导致微生物组多样性增加的环境因素已被证实与特应性疾病风险的大幅降低有关。与高风险人群相比，低过敏风险人群的系统，开发生物标志物 “保护性”免疫发育和评估对微生物组的免疫反应是基础设计和评估未来的干预措施在本提案中，我们将比较旧秩序门诺派。 (OOM) 食物过敏 (<1%)、其他过敏性疾病和哮喘以及生活方式的风险非常低与多样化的微生物群相关（例如在农场长大、食用生奶、大家庭、家庭分娩、抗生素使用率低），以及有食物过敏儿童的家庭所生的新生儿患特应性疾病的风险非常高，例如，出生后第一年有 15-20% 的风险发生食物过敏。我们认为 IgA 粘膜免疫的加速发展将成为“保护性”的生物标志物免疫发育在生命早期和动物模型数据中可见到大量 IgA 包被的粪便细菌。表明微生物多样性在诱导这种分泌性 IgA 中的重要性。 IgE 抗体（“特应性”）发展的倾向与 IgA 发展缓慢有关反应，例如我们自己的数据显示，对牛奶过敏的婴儿特定 IgA 的发育延迟。口服诱导耐受试验中令人兴奋的新发现进一步支持了特定 IgA 的作用因为肠道微生物群落存在密切的相互发展关系。凭借 IgA 库，我们勇敢地面对粘膜暴露于多样化且具有免疫原性的微生物群加速 IgA 分泌免疫的发展，抵消 IgE 反应的发展，以及预防过敏性疾病。我们将评估 B 细胞亚群、免疫球蛋白库和体细胞突变率（目标 1）以及肠道如何微生物组和 IgA 抗体对微生物组的反应在高过敏风险和低过敏风险人群中发展（目标 2），以及这些 B 细胞生物标志物和肠道微生物组如何与食物和其他物质的发育相关过敏性疾病和对过敏原的体液反应（目标 3）总之，该提案将确定。 IgA 反应的加速发展是否是“保护性”免疫发展的生物标志物，识别诱导 IgA 反应的粪便细菌，并评估特定 IgA 免疫反应的关联具有临床耐受性，即预防早发性食物过敏和湿疹。