Absorption of maternal antibodies from the gastrointestinal tract

描述（由申请人提供）：母乳喂养期间母婴传播免疫的概念源于Paul Ehrlich于1892年发表的经典研究。他的实验表明，由具有免疫能力的母鼠（而不是它们自己的母鼠）喂养的非免疫母鼠的后代获得了六周的毒素攻击保护。这种抗毒素（抗体）存在于母乳中，显然可以畅通无阻地通过肠壁进入新生儿的血液循环(4)。埃利希假设，这解释了为什么哺乳的新生儿在生命的第一年里经常免受感染。我们现在知道，新生儿Fc受体（FcRn）从肠腔携带大量摄入的母体IgG穿过肠道，在母乳喂养的后代中进入循环。此外，已经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了对传染性病原体的保护性免疫(5)。然而，值得赞赏的是，在新生儿中母体抗体的作用机制中存在额外的复杂性(6)。例如，母乳将过敏或自身免疫病理从母亲传给孩子（5;7;8）为更详细地了解新生儿生命中肠道中抗体摄取的关键介质提供了令人信服的论据。这在已确定的治疗靶点（FcRn）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，从而改善儿童健康。在我们的研究过程中，我们定义了哮喘发展中母体耐药传播的关键介质，我们测量了由过敏养母喂养的fcrn缺陷和fcrn充足的后代摄入的母体抗体水平。令我们惊讶的是，与FcRn后代相比，FcRn-/-对过敏原特异性IgG1的吸收预期会减少(9)，在母乳喂养的FcRn-/-小鼠中，母体对过敏原特异性IgA和IgE的吸收实际上是缺失的。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纯化的放射性标记抗体，显示肠道对IgG的摄取，但对IgA、IgE、IgM或IgD则没有（10）。这为最终鉴定FcRn的集中努力奠定了基础（11;12）。这种免疫机制似乎并没有在寄养护理实验中被重新检验，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在控制IgA或IgE的半衰期方面没有作用，尽管它在体内保护所有IgG同型不被降解方面起着关键作用(9)。在这个探索性应用中，我们将解决似乎不一致的观察结果，以确定FcRn在母体胃肠道吸收IgA或IgE中的作用。因此，我们提出：目标1。确定FcRn是否与IgA或IgE结合以促进胞吞和肠腔吸收；和Aim 2。确定免疫复合物是否提供了一个支架来增强新生儿胃肠道中fcrn介导的IgA或IgE摄取。

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.