Pregnancy influences maternal immune cell function and fetal brain development

怀孕影响母体免疫细胞功能和胎儿大脑发育

• 批准号: 10011840
• 负责人: Jun R. Huh
• 金额: $ 66.04万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011840
• 关键词: Adoptive Transfer; Adult; Affect; Anti-Inflammatory Agents; Autoimmune Diseases; Bacteria; Behavioral; Birth; Blocking Antibodies; Brain; Brain Pathology; Brain region; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Child; Communities; Development; Effector Cell; Embryo; Excision; Exposure to; Female; Fetus; Genes; Genetic; Human; Immune; Immune response; Immune system; Immunologic Tests; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukins; Intestines; Kinetics; Lead; Maps; Mediating; Mediator of activation protein; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Nuclear Orphan Receptor; Pathway interactions; Patients; Phenotype; Plasma; Play; Population; Pregnancy; Pregnant Women; Preventive; Preventive measure; Process; Production; Regulatory T-Lymphocyte; Reporting; Retinoic Acid Receptor; Rodent Model; Role; Second Pregnancy Trimester; Somatosensory Cortex; Specificity; T-Lymphocyte; Testing; Therapeutic; Translating; associated symptom; autistic; bacterial community; behavioral phenotyping; commensal bacteria; cytokine; epidemiology study; fetal; immune activation; mouse model; offspring; pregnancy failure; pregnant; prenatal; prevent; relating to nervous system; repetitive behavior; response; social deficits; targeted treatment; transcription factor

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.

抽象的 人类流行病学研究表明，胎儿在妊娠晚期暴露于母体炎症环境中。 或妊娠中期出现神经发育障碍的可能性增加。需要研究 定义怀孕期间免疫激活转化为免疫激活的分子和细胞机制 儿童神经发育和行为异常。 使用母体免疫激活 (MIA) 小鼠模型，我们证明 Th17 细胞至关重要 在受影响的后代中诱导神经发育障碍样表型的介质 产前炎症。我们还证明炎症引起的神经发育障碍 后代的表型需要母体肠道细菌，例如分段丝状细菌（SFB） 促进 Th17 细胞分化。此外，我们还绘制了大脑区域的空间和功能图 介导行为异常。 然而，人类怀孕期间的炎症并不一定会导致生出患有以下疾病的孩子： 神经发育障碍，表明存在抑制母体 Th17 细胞依赖性的因素， 受影响的后代出现神经发育障碍样表型。我们假设怀孕- 免疫细胞功能和共生细菌组成的相关变化有利于抗- 炎症反应决定了针对感染的免疫反应的幅度和特异性 和其他炎症状况。 在拟议的应用中，我们将首先确定妊娠引起的免疫细胞功能的变化和 它们对后代 MIA 样表型的影响。其次，我们会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 提出通过利用与妊娠相关的抗炎反应，我们可以开发预防性方法 抑制受 MIA 影响的后代的神经元和行为变化的方法。