Absorption of maternal antibodies from the gastrointestinal tract

描述（由申请人提供）：母乳喂养期间从母亲到后代的传染性免疫的概念起源于Paul埃利希在1892年发表的经典研究。他的实验表明，非免疫母鼠的后代由免疫养母（但不是它们自己的母亲）喂养，可以获得六周的毒素攻击保护。抗毒素（抗体）存在于母乳中，显然可以不受阻碍地穿过肠壁进入新生儿的血液循环（4）。埃利希假设，这解释了哺乳期新生儿在生命的第一年如何如此频繁地免受感染。我们现在知道，新生儿Fc受体（FcRn）携带大部分摄入的母体IgG从肠腔穿过肠道，在那里它进入母乳喂养后代的循环。此外，已确定这些被动吸收的母体抗体在新生儿自身免疫能力之前为新生儿提供了对感染因子的保护性免疫力（5）。然而，应当理解，母体抗体在新生儿中的作用机制存在额外的复杂性（6）。例如，过敏或自身免疫性疾病从母亲到孩子的母乳传播（5;7;8）为更详细地了解新生儿肠道中抗体摄取的关键介质提供了令人信服的论据。在确定的治疗靶点（FcRn）的出现时尤其如此，该靶点有可能增强或阻止母体抗体的递送，作为改善儿童健康的一种手段。在我们的研究过程中，我们定义了哮喘发展中母体抵抗力传播的关键介质，我们测量了过敏养母喂养的FcRN缺陷和充足后代中摄入的母体抗体水平。令我们惊讶的是，与FcRn后代相比，除了预期FcRn-/-对变应原特异性IgG 1的吸收减少外（9），母乳喂养的FcRn-/-小鼠中几乎不存在吸收的母体变应原特异性伊加和IgE。20世纪70年代在大鼠中进行的实验使用了从骨髓瘤患者血清中纯化的放射性标记抗体，以显示肠道对IgG的摄取，而不是伊加、IgE、IgM或IgD（10）。这为最终鉴定FcRn（11;12）的重点工作提供了基础。在寄养实验中，似乎没有重新检查这种免疫机制，以量化FcRn缺陷小鼠从母乳中吸收的母体伊加或IgE水平。然而，许多实验室已经证明，FcRn对伊加或IgE的半衰期没有控制作用，尽管其在保护所有IgG同种型免于体内降解方面具有关键作用（9）。在本探索性应用中，我们将解决似乎不一致的观察结果，以确定FcRn在胃肠道吸收母体伊加或IgE中的作用。因此，我们建议：目标1。确定FcRn是否结合伊加或IgE以促进从肠腔的转胞吞作用和吸收;以及目的2.确定免疫复合物是否提供支架以增强新生儿胃肠道中FcRn介导的伊加或IgE摄取。 公共卫生相关性：新生儿IgG Fc受体（FcRn）介导母亲向儿童传播免疫力，为儿童提供早期感染保护。我们的初步数据挑战了对FcRn生物学基本理解的基本概念，FcRn是一种具有巨大治疗潜力的分子靶点，对儿童和成人的健康产生积极影响。

DESCRIPTION (provided by applicant): The concept of transmissible immunity from mother to offspring during breastfeeding originated from the classic studies of Paul Ehrlich published in 1892. His experiments showed that offspring of non-immune mother mice nursed by immune foster mothers (but not their own mothers) acquire six weeks of protection from toxin challenge. The anti-toxin (antibody) was present in the mother's milk, passing apparently unhindered across the intestinal wall into the circulation of the newborn (4). Ehrlich hypothesized that this explained how the suckling newborn is so frequently protected from infections during the first year of life. We now know that the neonatal Fc receptor (FcRn) carries the bulk of ingested maternal IgG from the gut lumen across the intestine where it enters the circulation in breastfed offspring. Furthermore, it is established that these passively absorbed maternal antibodies provide neonates with protective immunity to infectious agents at a time prior their own immune competence (5). However, it is appreciated that there are additional complexities in the mechanism of action of maternal antibodies in neonates (6). For example, the breast milk transmission of allergic or autoimmune pathology from mother to child (5;7;8) provides a compelling argument for more detailed understanding of critical mediators of antibody uptake operational in the intestine in neonatal life. This is especially true in the advent of an identified therapeutic target (FcRn) with potential to enhance or prevent delivery of maternal antibodies as a means to improve child health. In the course of our studies to define critical mediators in maternal transmission of resistance from development of asthma, we measured the levels of ingested maternal antibodies in FcRn-deficient and -sufficient offspring nursed by allergic foster mothers. To our surprise, in addition to the expected decrease in the absorption of allergen-specific IgG1 by FcRn-/- compared to FcRn offspring (9), was the virtual absence of absorbed maternal allergen-specific IgA and IgE in breastfed FcRn-/- mice. Experiments performed in rats in the 1970s used radiolabeled antibodies purified from serum of myeloma patients to show intestinal uptake of IgG, but not IgA, IgE, IgM or IgD (10). This provided the foundation for the focused effort that ultimately led to the identification FcRn (11;12). It does not appear that this immune mechanism has been reexamined in foster nursing experiments as a means to quantify levels of maternal IgA or IgE absorbed from breast milk by FcRn-deficient mice. However, it has been proven in many laboratories that FcRn plays no role controlling the half-life of IgA or IgE, despite its critical role in protecting all IgG isotypes from degradation in vivo (9). In this exploratory application, we will resolve what appear to be discordant observations to determine the role for FcRn in absorption of maternal IgA or IgE from the gastrointestinal tract. Thus, we propose: Aim 1. To determine whether FcRn binds IgA or IgE to facilitate transcytosis and absorption from the gut lumen; and Aim 2. To determine whether immune complexes provide a scaffold to enhance FcRn-mediated uptake of IgA or IgE in the neonatal gastrointestinal tract. PUBLIC HEALTH RELEVANCE: The neonatal Fc receptor for IgG (FcRn) mediates mother to child transmission of immunity, providing children with protection from infections in early life. Our preliminary data challenge fundamental concepts in the basic understanding of the biology of FcRn, a molecular target with tremendous therapeutic potential to positively impact health in children and adults.