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.

摘要 人类流行病学研究表明，胎儿暴露于母体炎症在晚期第一， 或妊娠中期的女性患神经发育障碍的可能性增加。的研究需要 定义怀孕期间免疫激活转化为 儿童神经发育和行为异常。 使用母体免疫激活（MIA）的小鼠模型，我们证明了Th 17细胞是关键的 介质，诱导神经发育障碍样表型的受影响的后代暴露于 产前炎症我们还证明了炎症诱导的神经发育障碍 后代中的表型需要母体肠道细菌，如分节丝状细菌（SFB） 促进Th 17细胞分化。此外，我们已经在空间和功能上绘制了大脑区域， 介导行为异常 然而，人类怀孕期间的炎症并不总是导致婴儿的出生， 神经发育障碍，这表明存在抑制母体Th 17细胞依赖性的因素， 神经发育障碍样表型在受影响的后代。我们假设怀孕- 免疫细胞功能和肠道细菌组成的相关变化有利于抗- 炎症反应决定了抗感染免疫反应的幅度和特异性 和其他炎症性疾病。 在提出的申请中，我们将首先确定妊娠诱导的免疫细胞功能变化， 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 我建议，通过利用妊娠相关的抗炎反应，我们可以开发预防性药物， 抑制受MIA影响的后代的神经元和行为变化的方法。