Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure
Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure
复制标题
DOI：
10.1186/s12974-020-1717-8
复制
发表时间：
2020-01-28
影响因子：
9.3
通讯作者：
Weinberg, Joanne
中科院分区：
文献类型：
--
作者：
Bodnar, Tamara S.;Raineki, Charlis;Weinberg, Joanne
背景证据表明，细胞因子失衡可能是许多神经发育障碍（包括精神分裂症和自闭症谱系障碍）缺陷的根源。值得注意的是，虽然临床研究已经证明了母亲细胞因子的不平衡与酒精消费在怀孕期间，从动物模型的数据已经确定了免疫紊乱的酒精暴露的后代，到目前为止，酒精暴露的儿童的免疫改变还没有被探讨。因此，在这里，我们假设，由于产前酒精暴露导致的免疫环境的扰动将编程发育中的免疫系统，并导致免疫功能障碍进入儿童期。由于细胞因子在大脑发育/功能中的重要作用，我们进一步假设儿童免疫特征可能与其神经发育状态相关。方法作为乌克兰纵向研究的一部分，报告母亲在怀孕期间饮酒量低/无或中度至重度饮酒的儿童参加了这项研究，并接受神经发育评估。根据母亲饮酒量和儿童神经发育状况进行分组，结果分为以下几组：A/TD，饮酒母亲，通常发育中的儿童; A/ND，饮酒母亲，儿童神经发育迟缓; C/TD，对照母亲（低/无酒精消耗），通常发育中的儿童;和C/ND，对照母亲，儿童神经发育迟缓。在血浆中测量40种细胞因子/趋化因子，并使用回归和约束主成分分析来分析数据。结果分析显示，差异细胞因子网络活动与产前酒精暴露和神经发育状态。具体来说，酒精暴露的儿童表现出激活的细胞因子网络，包括嗜酸性粒细胞趋化因子-3，eotaxin，和bFGF，无论神经发育状态。然而，基于神经发育结果，另一种细胞因子网络被差异激活：A/TD显示MIP-1 β、MDC和MCP-4的激活，以及CRP和PlGF的抑制，在A/ND组中检测到相反的激活/抑制模式。相比之下，在没有酒精暴露的情况下，包括IL-2，TNF-β，IL-10和IL-15在内的网络的激活与神经发育延迟相关。总之，这种免疫标志物的综合评估允许识别与酒精暴露相关的独特免疫环境，以及酒精相关和酒精非依赖性神经发育迟缓。这些发现是建立酒精相关和酒精非依赖性神经发育迟缓的独特免疫生物标志物的关键一步。
Background Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. Methods As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. Results Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1 beta, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-beta, IL-10, and IL-15 was associated with neurodevelopmental delay. Conclusions Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.