The influence of maternal antibodies on neonatal intestinal immunity

新生儿免疫系统如何在最初获得微生物区系期间避免炎症反应 目前仍不清楚。建立肠道内环境平衡对新生儿来说尤其具有挑战性，因为他们 免疫系统还没有完全发育。这个应用程序的目标是调查母性 抗体指示新生儿免疫系统限制T细胞对新获得的微生物抗原的反应 在肠子里。这一建议建立在我们的发现之上，即母亲产生不依赖T细胞的IgG2b和 IgG3抗体与微生物区系起反应，并将这些抗体传递给子宫内和通过子宫的后代 母乳。没有接受任何母体抗体的新生小鼠表现出更多的移位 共生细菌穿过肠道屏障，对粘膜发起不适当的T细胞反应 抗原，在生命的头几个星期重量更轻。类似的缺陷在新生儿中也很明显，只有缺乏 母体IgG2b和IgG3，表明这些同功型是维持肠道内环境稳定所必需的 在生命的早期。值得注意的是，如果新生儿在实验上被迫获得T依赖的IgG2c抗体 一旦与微生物区系发生反应，它们就会遭受严重的死亡率和发病率。因此，我们的初步结果 表明新生儿从母亲那里获得的抗体类型会极大地影响健康。 在生命的头几周。这一提议将确定不同的免疫球蛋白亚型 抑制或增强新生儿对微生物区系的反应。此外，我们将确定是否具体 在缺乏母体免疫球蛋白抗体的情况下或在 获得性炎性免疫球蛋白G亚型。总体而言，本提案中描述的研究将揭示 微生物区系反应性母体抗体调节新生儿对微生物区系的免疫。

How the neonatal immune system avoids inflammatory responses during initial acquisition of the microbiota remains unclear. Establishing intestinal homeostasis is particularly challenging for neonates because their immune systems have not fully developed. The goal of this application is to investigate how maternal antibodies instruct the neonatal immune system to limit T cell responses to newly acquired microbial antigens in the intestine. This proposal builds on our discovery that mothers generate T cell-independent IgG2b and IgG3 antibodies reactive with the microbiota and pass these antibodies to their offspring in utero and through breastmilk. Newborn mice that do not receive any maternal antibodies show increased translocation of commensal bacteria across the intestinal barrier, mount inappropriate T cell responses against mucosal antigens, and weigh less for the first few weeks of life. Similar defects are apparent in neonates that only lack maternal IgG2b and IgG3, demonstrating that these isotypes are required to maintain intestinal homeostasis early in life. Remarkably, if neonates are experimentally forced to acquire T-dependent IgG2c antibodies reactive with the microbiota, then they suffer significant mortality and morbidity. Thus, our preliminary results indicate that the type of antibody acquired by neonates from their mothers can dramatically impact health during the first weeks of life. This proposal will determine the mechanism by which different IgG isotypes suppress or enhance responses to the microbiota in neonates. In addition, we will determine whether specific bacteria drive the immune dysregulation observed in the absence of maternal IgG antibodies or when inflammatory IgG isotypes are acquired. Overall, the studies described in this proposal will reveal how microbiota-reactive maternal antibodies regulate neonatal immunity to the microbiota.