母体免疫球蛋白D(IgD)跨胎盘转运的机制与抵御新生儿食物过敏的功能

Infections and allergies are major causes of neonatal morbidity and/or mortality. These conditions can be serious or fatal, and are associated with long-term diseases, imposing heavy social and economic burdens. Vaccination of pregnant women aimed at protecting neonates has drawn wide governmental, academic and industrial interests across the world. Maternal vaccination has always focused on vaccine-induced immunoglobulin G (IgG) antibody that can be transferred across the placenta to the fetus in pregnancy, but studies have suggested a limited role of IgG in early protection against many respiratory infections. 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 the mysterious antibody immunoglobulin D (IgD). We have pioneered the studies of IgD by showing that IgD is important in respiratory immune defense via inhibiting bacteria mucosal adhesion and activating antimicrobial and immune-amplifying functions of basophils, which may provide early and rapid protection during a respiratory infection. IgD activation of basophils and mast cells also suppresses IgE-induced allergic responses, 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 objective of this study is to determine the cellular and molecular mechanisms by which IgD is transported across the placenta, and the function of maternal IgD in promoting neonatal immune protection against and food allergy. We hypothesize that maternal IgD specific to vaccines or food undergoes placental transfer via a cellular pathway involving its delivery from the apical surface to the trans-Golgi network (TGN) in trophoblasts, where IgD is further sorted to the basolateral surface. We further contend that maternal food-specific IgD acts as a specific and prophylactic fetal immune education cue to protect neonates against food allergy by inhibiting the allergic functions of basophils and mast cells. Our study is expected to not only 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 IgD monoclonal antibody-based adoptive immunotherapies to combat neonatal infection and food allergy.

呼吸道感染和过敏是影响新生儿健康的重要原因。当今很多国家为孕妇接种疫苗，以诱导IgG抗体为新生儿提供早期保护。IgG被认为是唯一能跨胎盘转运的抗体，但实验表明其在呼吸道感染早期的保护作用有限。人上呼吸道粘膜富含IgD，其还可被分泌到血液中。我们在人和小鼠中的一系列前期研究发现，IgD在抵御呼吸道感染和过敏中有特殊的功能。近期，我们率先发现，孕期接种的百日破 (TDaP) 疫苗和摄入的食物在孕妇体内均可诱导特异性IgD的产生和跨胎盘转运。基于我们的前期研究，在此项目中，我们拟采用生物化学、细胞生物学、组织病理学和免疫学等方法在人和小鼠模型中揭示母体IgD跨胎盘转运的细胞与分子机制和其对新生儿食物过敏的保护功能。此研究不仅可能确立IgD是一种新的可跨胎盘的且有独特功能的抗体，也可指导IgD靶向母体疫苗的设计和单克隆抗体的研制，促进新生儿呼吸道感染与过敏的特异性预防与治疗。

背景：.过敏是新生儿发病和死亡的主要原因之一，可以导致沉重的社会和经济负担。针对新生儿食物过敏，避免或更换导致过敏的食物一直是最有效的管理策略，但由于某些食物的成分无处不在，这一策略往往很难实现。近年来，使用低剂量过敏原免疫来诱导阻断抗体例如免疫球蛋白G（IgG）和免疫球蛋白A（IgA），并引发调节性免疫细胞以使过敏患者脱敏的免疫疗法在儿童和成人患者中取得了一定疗效。 IgG可以在怀孕期间穿过胎盘并保护新生儿免受感染，但母体来源的IgG在保护新生儿免受过敏方面的作用和机制还有待了解。除此以外，母体 IgE 也可以穿过胎盘，使胎儿致敏，并在婴儿首次接触过敏原时介导过敏反应。除了 IgG 和 IgE 之外，我们在人和小鼠中发现怀孕期间接种的破伤风、白喉和百日咳 (TDaP) 疫苗诱导的母体 免疫球蛋白D（IgD）也会通过胎盘转移到胎儿体内。我们前期针对IgD的开创性研究表明 IgD 在呼吸道免疫防御中具有重要作用，还发现激活嗜碱性粒细胞和肥大细胞表面结合的IgD可以抑制 IgE 诱导的过敏反应； 在食物过敏儿童经口服免疫治疗后， 食物过敏原特异性 IgD 的增加与对过敏的保护成正相关。这些结果表明 过敏原特异性IgD对食物过敏具有保护作用。本课题研究母体来源的IgD 是否在防御新生儿食物过敏方面具有保护作用。..方法：.收集临产时妇女的外周血和分娩时的脐带血。他们的婴儿被随访直至2年，以监测对食物过敏症状的发展。那些有症状的人接受了皮肤点刺试验，以确定对特定食物的反应。通过 ELISA 测量母体外周血和脐带血总 IgD 和食物过敏原特异性 IgD。..结果：.母体总IgE、IgD和IgG4水平与脐带血总IgE、IgD和IgG4水平呈正相关，表明母体IgE、IgD和IgG4在妊娠期间通过胎盘转移给胎儿。在 2岁内发生鸡蛋过敏的那些人的脐带血中卵类粘蛋白特异性 IgD 和 IgG4 水平较低，表明脐带血中卵类粘蛋白特异性 IgD 和 IgG4 预测 2岁内免受鸡蛋过敏。..意义：.来自母亲的食物过敏原特异的脐带血IgG4和IgD可能对新生儿食物过敏反应具有保护作用。