Pregnancy influences maternal immune cell function and fetal brain development

摘要 人类流行病学研究表明，胎儿在第一次妊娠晚期暴露于母体炎症 或者怀孕中期患神经发育障碍的可能性增加。需要研究 为了确定怀孕期间免疫激活转化为 儿童神经发育和行为异常。 利用母体免疫激活(MIA)的小鼠模型，我们证明了Th17细胞是至关重要的 暴露在受影响的子代中诱发神经发育障碍样表型的介体 产前发炎。我们还证明了炎症导致的神经发育障碍 子代的表型需要母体肠道细菌，如分段丝状细菌(SFB) 促进Th17细胞分化的物质。此外，我们已经在空间和功能上绘制了大脑区域 来调停行为异常。 然而，人类怀孕期间的炎症并不总是导致婴儿出生时患有 神经发育障碍，表明存在抑制母亲Th17细胞依赖的因素， 受影响后代的神经发育障碍样表型。我们假设怀孕- 免疫细胞功能和共生菌组成的相关变化有利于抗- 决定抗感染免疫反应幅度和特异性的炎症反应 以及其他炎症性疾病。 在建议的应用中，我们将首先确定怀孕引起的免疫细胞功能和 它们对后代MIA样表型的影响。其次，我们将调查是否与怀孕有关 母体肠道细菌群落的变化有助于抗炎反应。最后，我们 建议通过利用与怀孕相关的抗炎反应，我们可以开发出预防 抑制MIA影响子代神经元和行为变化的方法。

ABSTRACT Human epidemiological studies suggest that fetuses exposed to maternal inflammation during the late first or the second trimester have an increased likelihood of neurodevelopmental disorders. Studies are needed to define the molecular and cellular mechanisms by which immune activation during pregnancy translates into neurodevelopmental and behavioral abnormalities in children. Using a mouse model of maternal immune activation (MIA), we demonstrated that Th17 cells are critical mediators that induce neurodevelopmental disorder-like phenotypes in the affected offspring exposed to prenatal inflammation. We also demonstrated that inflammation-induced neurodevelopmental disorder phenotypes in the offspring require maternal intestinal bacteria such as segmented filamentous bacteria (SFB) that promote Th17 cell differentiation. Moreover, we have spatially and functionally mapped the brain regions that mediate behavioral abnormalities. Inflammation during pregnancy in humans, however, does not always lead to the birth of children with neurodevelopmental disorders, suggesting that there are factors that suppress maternal Th17 cell-dependent, neurodevelopmental disorder-like phenotypes in the affected offspring. We hypothesize that pregnancy- associated changes in immune cell function and the composition of commensal bacteria favor anti- inflammatory responses that dictate both the amplitude and specificity of immune responses against infection and other inflammatory conditions. In the proposed application, we will first determine the pregnancy-induced changes in immune cell function and their impact on MIA-like phenotypes in offspring. Secondly, we will investigate if pregnancy-associated changes in the bacterial community of the maternal guts contribute to anti-inflammatory responses. Lastly, we propose that by harnessing pregnancy-associated anti-inflammatory responses we can develop preventive ways to suppress neuronal and behavioral changes in the MIA-affected offspring.