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

• 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
• 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

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展中起着至关重要的作用 微生物组的多样性几乎可以肯定在过敏和自身免疫性疾病激增中起重要作用 在1950年代开始并持续到今天的发达国家中。生活在农场上，避免抗生素， 阴道传递和其他导致微生物组多样性更大的环境因素已经 与特应性疾病的风险大大降低有关。了解免疫的发展 与高风险人群相比 “保护性”免疫发育以及评估对微生物组的免疫反应是至关重要的 设计和评估未来的干预措施。在此提案中，我们将比较旧秩序的门诺派 （OOM）食物过敏的风险非常低（<1％），其他过敏性疾病和哮喘和生活方式 与潜水员微生物组相关（例如，在农场上长大，生牛奶的消费，大家庭， 家居分娩，抗生素使用率低）以及有食物过敏儿童的家庭出生的新生儿 患有特应性疾病的风险很高，例如在生命的第一年，食物过敏的风险为15-20％。 我们假设IGA粘膜免疫的加速发展将成为“保护”的生物标志物 免疫发育。在早期生命和动物模型的数据中可以看到丰富的Iga涂层粪便细菌 表明微生物多样性在诱导该秘密IgA中的重要性。早期研究表明 IgE抗体开发（“ Atopy”）的倾向与IgA的发展缓慢有关 响应，例如我们自己的数据显示，牛奶过敏婴儿中特定IgA的发展延迟。 令人兴奋的新发现进一步支持特定IgA的作用，来自对口服诱导耐受性的试验 已建立的食物过敏。因为肠道微生物群落有亲密的相互发展 使用IGA曲目，我们假设粘膜暴露于潜水员和免疫原性微生物组 加速IGA秘密免疫的发展，抵消IgE反应的发展，并 保护免受过敏性疾病。 我们将评估B细胞子集，免疫球蛋白库和体细胞突变率（AIM 1）和肠道如何 微生物组和IgA抗体对高危人群中微生物组发育的反应 （AIM 2），以及这些B细胞生物标志物和肠道微生物组与食物和其他的开发有关 过敏性疾病和对过敏原的体液反应（AIM 3）。总而言之，该提议将确定 IGA反应的加速发展是否是“保护”免疫发育的生物标志物， 鉴定诱导IgA反应的粪便细菌，并评估特定IgA免疫回报的关联 具有临床耐受性，即防止早期发作的食物过敏和湿疹。