Breastmilk antibodies regulate neonatal immunity to the microbiota

项目总结 为了保持健康，宿主必须避免对有益的肠道细菌产生炎症反应，而 保持对病原体做出反应的能力。在早期生活中，维持这种平衡尤其复杂，因为 许多有助于促进成人对常驻共生微生物的耐受性的机制是 在此期间缺席的或尚未确立的。我们最近发现母源抗体是母体抗体的关键调节因子 新生儿的宿主-微生物区系互惠关系。具体地说，我们发现，除了IgA，健康的母亲还会产生 微生物区系反应性的免疫球蛋白抗体，通过母乳和新生儿肠道中的被毛细菌传播。在……里面 与对照后代相比，没有接受这些母体同型的新生儿有更多的风险 肠道引流淋巴结中的共生细菌数量，安装不适当的微生物区系驱动的CD4T- 依赖免疫反应，并遭受更高的发病率时，受到化学形式的结肠炎。 基于这些令人兴奋的发现，这项提议试图理解母体 抗体调节新生儿的新生宿主-微生物区系的相互作用。具体地说，我们将确定抗原 所需的特异性和效应机制(例如，补体激活或Fc受体连接) 不同的母体免疫球蛋白同型抑制新生儿对有益肠道细菌的适应性免疫反应。 此外，我们将定义触发失调适应性所需的信号通路和细胞类型 没有收到母乳抗体的后代的免疫反应。我们将采用创新的方法 通过利用转基因小鼠培育和优化婴儿喂养方法来实现这些目标 模型和多参数流式细胞术。这些研究具有重要意义，因为它们解决了我们在 关于如何在寄主和寄生微生物群之间建立良好关系的知识 早年的生活。此外，我们的工作还将促进我们对母乳喂养机制的理解 促进健康。我们预计，从这项研究中获得的洞察力将大大有助于我们 在生命早期操纵宿主-微生物群的相互作用和粘膜免疫，而不考虑营养模式。

PROJECT SUMMARY To maintain health, the host must avoid generating inflammatory responses to beneficial gut bacteria, while retaining the ability to respond to pathogens. Maintaining this balance is particularly complicated in early life as many of the mechanisms that serve to promote tolerance to resident commensal microbes in adults are either absent or not yet established during this period. We recently identified maternal antibodies as key regulators of host-microbiota mutualism in neonates. Specifically, we found that in addition to IgA, healthy mothers generate microbiota-reactive IgG antibodies, which are transmitted via breastmilk and coat bacteria in the neonatal gut. In comparison with control offspring, neonates that do not receive these maternal isotypes harbor increased numbers of commensal bacteria in gut draining lymph nodes, mount inappropriate, microbiota-driven CD4 T- dependent immune responses, and suffer increased morbidity when subjected to a chemical form of colitis. Building from these exciting findings, this proposal seeks to understand the mechanisms by which maternal antibodies regulate nascent host-microbiota interactions in neonates. Specifically, we will determine the antigen specificities and the effector mechanisms (e.g., complement activation or Fc receptor ligation) required for distinct maternal IgG isotypes to restrain neonatal adaptive immune responses to beneficial gut bacteria. Additionally, we will define the signaling pathways and cell types required to trigger dysregulated adaptive immune responses in offspring that do not receive breastmilk antibodies. We will employ innovative approaches to achieve these goals by leveraging fostering and optimized infant feeding approaches with transgenic mouse models and multi-parameter flow cytometry. These studies are significant because they address key gaps in our knowledge regarding how favorable relationships between the host and resident microbiota are established in early life. Additionally, our work will also advance our understanding of the mechanisms by which breastfeeding promotes health. We expect that the insight gained from this research will significantly aid in our ability to manipulate host-microbiota interactions and mucosal immunity during early life, regardless of mode of nutrition.