Molecular Epidemiology Unit, Charité - Universitátsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, associated partner of the German Center for Lung Research (DZL), Berlin, Germany.
Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany.
Front Immunol. 2019 Jul 23;10:1658. doi: 10.3389/fimmu.2019.01658. eCollection 2019.
Maternal immune activation (MIA) during fetal development leads to behavioral and psychological disorders in the offspring. Concomitantly, insufficient supply of polyunsaturated fatty acids (PUFAs) is suspected to contribute to early neuronal maldevelopment due to the immune modulatory capabilities of PUFAs. However, human data are missing considering both of these aspects and their impact on children's behavioral outcomes. In line, this study aimed to elucidate the influence of gestational cytokines and PUFA-containing lipids during late pregnancy on behavioral sequelae in childhood, particularly focusing on an immune activation shaped by a history of maternal atopic diseases instead of a pathogen-mediated immune response. Based on the prospective mother-child cohort LINA we assessed the unstimulated blood cytokine profiles and concentrations of PUFA-containing lipids of 293 mothers at the 34th week of pregnancy. Maternal history of atopic diseases was obtained from questionnaires and behavior in eight-year-old children was assessed by the standardized Strength and Difficulties Questionnaires (SDQ) generating scores for hyperactivity/inattention, emotional symptoms, conduct problems, and peer relationship problems. Elevated IL-13 increased the risk for the child to show behavioral difficulties, in particular, hyperactive/inattentive behavior [adj. OR (95% CI): 2.47 (1.51-4.02), = 255 vs. 38] at the age of eight years. Although the presence of maternal atopic dermatitis (AD) was associated with increased gestational IL-13 concentrations [adj. MR (95% CI): 1.17 (1.04-1.32)], no effect on children's behavioral difficulties was observed. However, a decrease in the PUFA containing lipid species PC aa C38:6 was not only associated with an increased gestational IL-13 concentration but also mediated the indirect effect of low PC aa C38:6 concentrations on children's abnormal behavior independent of maternal AD. We additionally assessed whether maternal IL-13 and PC aa C38:6 concentrations translate their effect by altering children's cord blood PC aa C38:6 and IL-13. While also the children's cord blood IL-13 was related to children's behavior, no effect of children's PC aa C38:6 was observed. This is the first study demonstrating that elevated gestational IL-13 increases the risk for children to develop behavioral difficulties. Analyses suggest that a reduced supply of gestational PC aa C38:6 contributes to elevated gestational IL-13 leading to behavioral sequelae in the offspring.
母体免疫激活（MIA）在胎儿发育过程中导致后代出现行为和心理障碍。同时，由于多不饱和脂肪酸（PUFA）的免疫调节能力，人们怀疑 PUFA 的供应不足会导致早期神经元发育不良。然而，考虑到这两个方面及其对儿童行为结果的影响，人类数据仍然缺失。因此，本研究旨在阐明妊娠晚期细胞因子和含多不饱和脂肪酸的脂质对儿童行为后遗症的影响，特别是关注由母体特应性疾病史引起的免疫激活，而不是由病原体介导的免疫反应引起的免疫激活。基于前瞻性母婴队列 LINA，我们评估了 293 名孕妇在妊娠第 34 周时未刺激血液细胞因子谱和含多不饱和脂肪酸脂质的浓度。母体特应性疾病史通过问卷调查获得，8 岁儿童的行为通过标准化的《长处与困难问卷》（Strength and Difficulties Questionnaires，SDQ）进行评估，该问卷产生多动/注意力不集中、情绪症状、行为问题和同伴关系问题的分数。升高的 IL-13 增加了孩子出现行为困难的风险，特别是多动/注意力不集中的行为[调整后的 OR（95%CI）：2.47（1.51-4.02），= 255 比 38]，在 8 岁时。尽管母体特应性皮炎（AD）的存在与升高的妊娠 IL-13 浓度相关[调整后的 MR（95%CI）：1.17（1.04-1.32）]，但对儿童的行为困难没有影响。然而，含多不饱和脂肪酸的脂质 PC aa C38:6 水平的降低不仅与妊娠 IL-13 浓度的升高相关，而且还介导了低 PC aa C38:6 浓度对儿童异常行为的间接影响，而与母体 AD 无关。我们还评估了母体 IL-13 和 PC aa C38:6 浓度是否通过改变儿童脐带血 PC aa C38:6 和 IL-13 来发挥其作用。虽然儿童脐带血 IL-13 也与儿童行为有关，但没有观察到儿童 PC aa C38:6 的影响。这是第一项表明升高的妊娠 IL-13 增加了儿童出现行为困难的风险的研究。分析表明，妊娠期间 PC aa C38:6 供应减少导致妊娠 IL-13 升高，从而导致后代出现行为后遗症。
