Development of Mucosal and Systemic Immunity and Risk of Food Allergy

微生物组在免疫系统的发展和免疫系统的改变中起着关键作用。 微生物群的多样性几乎肯定在变态反应性和自身免疫性疾病的激增中起着重要作用。 在发达国家，始于20世纪50年代的S一直延续到今天。住在农场，避免使用抗生素， 阴道分娩和其他环境因素导致微生物组更大的多样性 与显著降低特应性疾病的风险有关。理解免疫的发展 与高危人群相比，低风险过敏人群的系统，开发用于 “保护”免疫发展和评估对微生物组的免疫反应是 设计和评估未来的干预措施。在这个提案中，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的风险非常低，以及一种生活方式 与不同的微生物群相关(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出生的新生儿 患特应性疾病的风险非常高，例如，在生命的第一年有15%-20%的食物过敏风险。 我们推测，免疫球蛋白A粘膜免疫的加速发展将是“保护性”的生物标志物。 免疫发育。在早期生命和动物模型数据中发现了丰富的IgA包裹的粪便细菌 表明微生物多样性在诱导这种分泌型IgA中的重要性。早期的研究表明 易发展的IgE抗体(“特应性”)与发展缓慢的IgA有关 反应，例如，我们自己的数据显示，牛奶过敏婴儿中特异性IgA的发育延迟。 令人兴奋的新发现进一步支持来自口服诱导耐受试验的特定IgA的作用 已确定的食物过敏。因为肠道微生物群落之间存在着一种密切的相互发展 根据免疫球蛋白A谱系，我们假设粘膜接触到一个多样化的免疫原性微生物群 促进免疫球蛋白A分泌性免疫的发展，对抗免疫球蛋白E反应的发展 保护您免受过敏性疾病侵袭。 我们将评估B细胞亚群、免疫球蛋白谱系和体细胞突变率(目标1)和肠道 微生物组和IgA抗体对微生物组的反应在变态反应高危和低危人群中发生 (目标2)，以及这些B细胞生物标记物和肠道微生物组如何与食品和其他 过敏性疾病和对过敏原的体液反应(目标3)。总之，这项提案将决定 免疫球蛋白A反应的加速发展是否是“保护性”免疫发展的生物标志物 鉴定引起IgA应答的粪便细菌，并评估特异性IgA免疫应答的相关性 具有临床耐受性，即防止早发性食物过敏和湿疹。

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.