Mechanism and function of transplacental IgD

项目摘要 过敏正在成为新生儿发病率的主要原因，食物过敏的发病率呈上升趋势 并显著影响幼儿，其中一些可能是严重的或致命的，并与长期- 长期发病率，造成沉重的社会和经济负担。对于新生儿食物过敏，没有有效的治疗方法 目前是可用的，除了避免或替换有害的食物，这通常是不可能的，因为 一些食物成分的无处不在的性质。因此，迫切需要找出有效的方法。 增强新生儿的免疫功能，改善其近期和长期健康状况。人类 呼吸道粘膜和血液分泌免疫球蛋白D(IGD)。我们发现IGD在 抑制病原体粘膜黏附、激活抗菌药物和抗菌药物的呼吸道免疫防御 嗜碱性粒细胞的免疫放大功能。嗜碱性粒细胞的IgD激活也能抑制IgE诱导的过敏反应 功能，增加食物过敏原特异性IGD的产生与预防食物过敏有关 儿童口服免疫治疗后。母体破伤风、白喉和无细胞百日咳(Tdap)疫苗和 孕期食物暴露诱导疫苗和食物特异性IGD的产生，并通过 胎盘在人类和小鼠体内对胎儿的作用。这里的目标是了解 胎盘转移IGD和确定母体IGD是否促进新生儿对食物的免疫保护 过敏。我们假设，针对疫苗或食物的母体免疫球蛋白D起到特定的预防性胎儿的作用 免疫教育提示保护新生儿免受食物过敏。值得注意的是，嗜碱性粒细胞的激活和抗- 过敏功能是IGD独有的，而不是Ig G所具有的。使用生化和成像技术 在细胞培养、人类胎盘标本和小鼠模型中，目标1中的研究将从机械上阐明 母体IGD的胎盘转移。目标2将确定母体食物特异性IGD在 整合免疫球蛋白E介导的新生小鼠模型对免疫球蛋白E介导的新生儿食物过敏的保护作用 新生儿脐带或外周血标本与食物引起的过敏反应 生命第一年的食物过敏。我们的研究有望揭示母体IGD的独特功能，以及 古老而神秘的抗体，在新生儿免疫功能中是母体免疫球蛋白所不具备的，也 通过指导针对IGD的母体设计对改善新生儿健康产生深远影响 疫苗或过继免疫疗法。

Project Summary Allergies are becoming a major cause of neonatal morbidity, with food allergies showing increased incidences and significantly affecting young infants, some of which can be serious or fatal, and are associated with long- term morbidity, imposing heavy social and economic burdens. For neonatal food allergy, no effective treatment is currently available except avoiding or replacing the offending food, which is often impossible due to the ubiquitous nature of some food components. Hence, there is a critical need to identify effective means of strengthening the immune function of neonates to improve their immediate and long-term health. Human respiratory mucosa and blood harbor secreted immunoglobulin D (IgD). We found that IgD is important in respiratory immune defense by inhibiting mucosal adhesion of pathogens and activating antimicrobial and immune-amplifying functions of basophils. IgD activation of basophils also suppresses IgE-induced allergic functions, and increased food allergen-specific IgD production correlates with protection against food allergy after oral immunotherapy in children. Maternal tetanus, diphtheria, and acellular pertussis (TDaP) vaccine and food exposure in pregnancy induces the production of vaccine- and food-specific IgD that is transferred across the placenta to the fetus in humans and mice. The objectives here are to understand the mechanisms of the placental transfer of IgD and to determine if maternal IgD promotes neonatal immune protection against food allergy. We hypothesize that maternal IgD specific to vaccines or food acts as a specific and prophylactic fetal immune education cue to protect neonates against food allergy. Of note, the basophil-activating and anti- allergic functions are unique to IgD and not possessed by IgG. Employing biochemical and imaging techniques in cell culture, human placenta specimens and mouse models, studies in Aim 1 will mechanistically elucidate the placental transfer of maternal IgD. Aim 2 will determine the function of maternal food-specific IgD in the protection against IgE-mediated neonatal food allergy by integrating neonatal mouse models of IgE-mediated food-induced anaphylaxis with human cord or peripheral blood specimens of newborn babies with or without food allergy in the first year of life. Our study is expected to reveal the unique functions of maternal IgD, an ancient yet still mysterious antibody, in neonatal immune function that maternal IgG does not have, but also have a profound impact on improving neonatal health by directing the design of IgD-targeting maternal vaccines or adoptive immunotherapies.