MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Brain Behav Immun. 2020 Nov;90:311-318. doi: 10.1016/j.bbi.2020.09.007. Epub 2020 Sep 10.
Preterm birth is associated with dysconnectivity of structural brain networks, impaired cognition and psychiatric disease. Systemic inflammation contributes to cerebral dysconnectivity, but the immune mediators driving this association are poorly understood. We analysed information from placenta, umbilical cord and neonatal blood, and brain MRI to determine which immune mediators link perinatal systemic inflammation with dysconnectivity of structural brain networks.
Participants were 102 preterm infants (mean gestational age 29 weeks, range 23-32). Placental histopathology identified reaction patterns indicative of histologic chorioamnionitis (HCA), and a customized immunoassay of 24 inflammation-associated proteins selected to reflect the neonatal innate and adaptive immune response was performed from umbilical cord (n = 55) and postnatal day 5 blood samples (n = 71). Brain MRI scans were acquired at term-equivalent age (41 weeks [range 38-44 weeks]) and alterations in white matter connectivity were inferred from mean diffusivity and neurite density index across the white matter skeleton.
HCA was associated with elevated concentrations of C5a, C9, CRP, IL-1β, IL-6, IL-8 and MCP-1 in cord blood, and IL-8 concentration predicted HCA with an area under the receiver operator curve of 0.917 (95% CI 0.841 - 0.993, p < 0.001). Fourteen analytes explained 66% of the variance in the postnatal profile (BDNF, C3, C5a, C9, CRP, IL-1β, IL-6, IL-8, IL-18, MCP-1, MIP-1β, MMP-9, RANTES and TNF-α). Of these, IL-8 was associated with altered neurite density index across the white matter skeleton after adjustment for gestational age at birth and at scan (β = 0.221, p = 0.037).
These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.
早产与结构脑网络的连通性中断、认知障碍和精神疾病有关。全身炎症导致大脑连通性中断，但驱动这种关联的免疫介质知之甚少。我们分析了胎盘、脐带和新生儿血液以及脑 MRI 的信息，以确定哪些免疫介质将围产期全身炎症与结构脑网络的连通性中断联系起来。
参与者为 102 名早产儿（平均胎龄 29 周，范围 23-32 周）。胎盘组织病理学确定了组织绒毛膜羊膜炎（HCA）的反应模式，并且从脐带（n=55）和出生后第 5 天的血液样本（n=71）中进行了针对 24 种炎症相关蛋白的定制免疫分析，这些蛋白被选择来反映新生儿的先天和适应性免疫反应。脑 MRI 扫描在胎龄相等时（41 周[范围 38-44 周]）进行，并且通过整个白质骨架的平均扩散率和神经丝密度指数推断出白质连通性的改变。
HCA 与脐带血中 C5a、C9、CRP、IL-1β、IL-6、IL-8 和 MCP-1 的浓度升高有关，IL-8 浓度的曲线下面积为 0.917（95%CI 0.841-0.993，p<0.001），可预测 HCA。14 种分析物解释了 66%的产后特征（BDNF、C3、C5a、C9、CRP、IL-1β、IL-6、IL-8、IL-18、MCP-1、MIP-1β、MMP-9、RANTES 和 TNF-α）。其中，IL-8 在调整出生时和扫描时的胎龄后与白质骨架的神经丝密度指数改变相关（β=0.221，p=0.037）。
这些发现表明，IL-8 失调在将围产期全身炎症与早产儿异常白质发育联系起来方面发挥作用。
