Microbial-induced maternal factors that influence fetal immune development

摘要 怀孕的免疫学是复杂和微妙的平衡。虽然不能耐受胎儿抗原 在怀孕期间可能导致胎儿丢失，对病原体的无效免疫可能威胁到两者的生存 胎儿和母亲胎儿组织和母体免疫系统不断沟通， 保持这种平衡。这项建议的重点是两个未充分研究的机制，母胎 通讯：细胞外囊泡（EV）-携带免疫调节蛋白和 细胞分泌的miRNAs和母体微嵌合细胞（MMc）-母体免疫的垂直转移 细胞移植到胎儿器官具体来说，我们的目标是了解这些过程是如何受到正常微生物的影响， 以更好地了解它们在正常妊娠期间的功能。我们对电动汽车的了解 和MMc在怀孕期间已经发现使用常规的无特定病原体（SPF）小鼠 这些模式的微生物多样性有限，几乎没有病原体。这些人工卫生的 环境条件与自然形成鲜明对比，在自然界中微生物无处不在且多种多样。的确，我们和其他人 已经证明，在SPF条件下饲养的小鼠的免疫系统相对于 对人类和野生/宠物店的老鼠。我们认为，在SPF中，EVs和MMc的性质和作用 怀孕由于缺乏多样的微生物经验而受到损害，从而降低了预测能力。 SPF研究。我们的实验室已经开发出一种孕前正常微生物体验（pNME）模型， 实验室小鼠在繁殖之前与宠物商店小鼠共同圈养， 微生物群落在整个妊娠期和早期生活中，共同生活会持续下去， “成熟”的母亲因素，并从最早的自然时间遇到不同的微生物复制正常 哺乳动物的免疫发育更准确。利用这个模型，我们发现免疫系统 的pNME小鼠被广泛扩展，并且比SPF小鼠更早地实现免疫发育里程碑。 pNME小鼠还显示出相对于SPF小鼠增强的存活和免疫防御。差距 传统SPF模型和自然免疫发育之间的免疫力导致了 对母胎免疫通讯和胎儿免疫机制的理解进展 发展拟议的研究描述了一种免疫发育的自然模型（pNME）， 将实验室小鼠品系的丰富资源和工具与生理微生物经验相结合， 更深入地了解正常母胎免疫通讯的机制及其 影响胎儿免疫发育。此外，这些实验将为改进 临床前模型研究免疫病理学的生物标志物、治疗和预防， 怀孕和早期生活。

ABSTRACT The immunology of pregnancy is complex and delicately balanced. While failure to tolerate fetal antigens during pregnancy can result in fetal loss, ineffective immunity to pathogens can threaten the survival of both the fetus and the mother. Fetal tissues and the maternal immune system continuously communicate to maintain this balance. This proposal focuses on two understudied mechanisms of maternal-fetal communication: extracellular vesicles (EVs) – lipid-bound particles carrying immunomodulatory proteins and miRNAs secreted by cells, and maternal microchimeric cells (MMc) – the vertical transfer of maternal immune cells to fetal organs. Specifically, we aim understand how these processes are influenced by normal microbial experience to better understand their function during normal pregnancies. Much of what we know about EVs and MMc during pregnancy has been discovered using conventional specific pathogen free (SPF) mouse models, which have limited microbial diversity and are nearly devoid of pathogens. These artificially hygienic conditions are in stark contrast to nature, where microbes are ubiquitous and diverse. Indeed, we and others have demonstrated that the immune systems of mice raised under SPF conditions are underdeveloped relative to humans and feral/pet store mice. We posit that the character and function of EVs and MMc in SPF pregnancies are impaired by the lack of diverse microbial experience, thus reducing the predictive power of SPF studies. Our lab has developed a preconception normal microbial experience (pNME) model whereby laboratory mice are cohoused with pet store mice prior to breeding to naturally expose them to the diverse microbial communities. Cohousing continues throughout gestation and early life, ensuring the offspring receive ‘mature’ maternal factors and encounter diverse microbes from the earliest natural time to replicate normal mammalian immune development more accurately. Using this model, we have found that the immune systems of pNME mice are broadly expanded and achieve immune developmental milestones earlier than SPF mice. pNME mice also demonstrate enhanced survival and immune defense relative to SPF mice. The gap in immunity between conventional SPF models and natural immune development has contributed to the slow progress toward mechanistic understanding of maternal-fetal immune communication and fetal immune development. The proposed research describes a natural model of immune development (pNME) that combines the ample resources and tools of laboratory mouse strains with physiological microbial experience to gain a deeper understanding of the mechanisms of normal maternal-fetal immune communication and their influence on fetal immune development. Further, these experiments will lay the groundwork for improved preclinical models investigating biomarkers, treatments, and preventions for immune pathologies during pregnancy and early life.