Absorption of maternal antibodies from the gastrointestinal tract

描述(申请人提供)：母乳喂养期间母亲向后代传播免疫的概念起源于1892年发表的Paul Ehrlich的经典研究。他的实验表明，由免疫养母(但不是自己的母亲)喂养的非免疫母鼠的后代可以获得六周的毒素攻击保护。抗毒素(抗体)存在于母乳中，显然不受阻碍地穿过肠壁进入新生儿的循环(4)。埃尔利希假设，这解释了哺乳新生儿在生命的第一年是如何如此频繁地免受感染的。我们现在知道，新生儿Fc受体(FcRN)携带大量被摄取的母体免疫球蛋白，从肠腔穿过肠道，进入母乳喂养的后代的循环。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其提供对感染性病原体的保护性免疫(5)。然而，人们认识到，在新生儿中母体抗体的作用机制还有额外的复杂性(6)。例如，从母亲到孩子(5；7；8)的过敏或自身免疫病理的母乳传播为更详细地了解新生儿生活中肠道抗体摄取的关键媒介提供了令人信服的论据。在已确定的治疗目标(FcRN)的出现时尤其如此，该目标有可能加强或防止母体抗体的交付，作为改善儿童健康的一种手段。在我们确定哮喘耐药性母体传播的关键介质的研究过程中，我们测量了由过敏性寄养母亲喂养的FcRN缺乏和足够的后代中摄入的母体抗体水平。令我们惊讶的是，除了FcRN-/-与FcRN-/-后代(9)相比，FcRN-/-对过敏原特异性IgG1的吸收预期减少之外，母乳喂养的FcRN-/-小鼠实际上缺乏吸收的母体过敏原特异性IgA和IgE。20世纪70年代在大鼠身上进行的实验使用了从骨髓瘤患者血清中提纯的放射性标记抗体来显示肠道摄取IgG，但没有显示IgA、IgE、IgM或IGD(10)。这为最终确定FcRN(11；12)的重点工作奠定了基础。这种免疫机制似乎没有在寄养护理实验中被重新检查，作为一种量化FcRN缺陷小鼠从母乳中吸收的母体IgA或IgE水平的手段。然而，许多实验室已经证明，FcRN对控制IgA或IgE的半衰期没有作用，尽管它在保护所有免疫球蛋白亚型不被体内降解方面发挥了关键作用。在这一探索性应用中，我们将解决一些似乎不一致的观察结果，以确定FcRN在从胃肠道吸收母体IgA或IgE方面的作用。因此，我们建议：目的1.确定FcRN是否与IgA或IgE结合以促进肠腔的跨细胞吸收；以及目的2.确定免疫复合物是否提供了一种支架，以增强FcRN介导的新生儿胃肠道对IgA或IgE的摄取。 公共卫生相关性：新生儿免疫球蛋白Fc受体(FcRN)介导母婴免疫传递，为儿童提供早期免受感染的保护。我们的初步数据挑战了对FcRN生物学的基本理解中的基本概念，FcRN是一种具有巨大治疗潜力的分子靶点，可以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.