BACKGROUND 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. METHODS Participants were 102 preterm infants (mean gestational age 29+1 weeks, range 23+3-32+0). 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+0 weeks [range 38+0 - 44+4 weeks]) and alterations in white matter connectivity were inferred from mean diffusivity and neurite density index across the white matter skeleton. RESULTS 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). CONCLUSIONS These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.

中文翻译：

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白细胞介素 8 失调与早产后脑发育不良有关

背景技术早产与结构性脑网络的连接障碍、认知障碍和精神疾病有关。全身性炎症会导致大脑连接障碍，但对驱动这种关联的免疫介质知之甚少。我们分析了来自胎盘、脐带和新生儿血液以及脑部 MRI 的信息，以确定哪些免疫介质将围产期全身炎症与结构性脑网络的连接障碍联系起来。方法 参与者为 102 名早产儿（平均胎龄 29+1 周，范围 23+3-32+0）。胎盘组织病理学确定了指示组织学绒毛膜羊膜炎 (HCA) 的反应模式，从脐带 (n=55) 和出生后第 5 天的血液样本 (n=71) 中选择来反映新生儿先天性和适应性免疫反应的 24 种炎症相关蛋白的定制免疫测定。脑 MRI 扫描是在足月等效年龄（41+0 周 [范围 38+0 - 44+4 周]）获得的，白质连接的改变是从白质骨骼的平均扩散率和神经突密度指数推断出来的。结果 HCA 与脐带血中 C5a、C9、CRP、IL-1β、IL-6、IL-8 和 MCP-1 浓度升高相关，IL-8 浓度预测 HCA，接受者操作曲线下面积为 0.917 (95% CI 0.841 - 0.993, p<0.001)。14 种分析物解释了 66% 的产后特征差异（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，在调整出生时和扫描时的胎龄后，IL-8 与整个白质骨骼的神经突密度指数改变相关（β = 0.221，p = 0.037）。结论 这些发现表明，IL-8 失调在将早产儿的围产期全身炎症和非典型白质发育联系起来中起作用。