Utility of chemokines CCL2, CXCL8, 10 and 13 and interleukin 6 in the pediatric cohort for the recognition of neuroinflammation and in the context of traditional cerebrospinal fluid neuroinflammatory biomarkers

BackgroundThe recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses.MethodsC-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p ResultsCompared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed.ConclusionsThe increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

背景：在未检测到病原体的情况下，识别中枢神经系统（Central Nervous System, CNS）的活动性炎症颇具挑战。本研究旨在明确五种选定的趋化/细胞因子在识别中枢神经系统炎症中的诊断价值，并结合传统脑脊液（Cerebrospinal Fluid, CSF）生物标志物——白细胞（White Blood Cell, WBC）计数、寡克隆带、蛋白水平、脑脊液/血清白蛋白比值——以及临床诊断开展分析。
方法：采用Luminex多重微球技术及配套软件，对37名对照个体与87名罹患10种不同（以非感染性为主）炎症性中枢神经系统疾病的有症状儿童的脑脊液及血清中的C-C基序配体、C-X-C基序配体（CCL2、CXCL8、CXCL10、CXCL13）以及白细胞介素6（Interleukin 6, IL-6）水平进行检测。其中16名患儿在康复后留有随访标本。本研究采用非参数检验，P值。
结果：与对照脑脊液标本相比，有症状患儿的脑脊液中所有检测的趋化/细胞因子水平均升高，且仅IL-6在康复标本中仍维持高水平（p ≤ 0.001）。脑脊液CXCL13水平（> 10.9 pg/mL）是区分神经炎症的最佳单一鉴别指标（在无脑脊液细胞增多症的标本中，其特异性/敏感性分别为97%/72%、97%/61%），其次为脑脊液白细胞计数（特异性/敏感性：97%/62%）。其余脑脊液趋化/细胞因子的临床应用价值按敏感性从高到低排序，对应阈值可确保在无脑脊液细胞增多症的标本中对神经炎症实现97%的特异性（单位：pg/mL；敏感性%）：IL-6（3.8；34）、CXCL8（32；26）、CXCL10（317；24）及CCL2（387；10）。研究同时观察到不同诊断相关的脑脊液趋化/细胞因子谱。
结论：在所有单独检测的生物标志物中，脑脊液CXCL13水平升高是用于全面识别神经炎症的最佳预测生物标志物。本研究明确了趋化/细胞因子在神经炎症性疾病鉴别诊断中的潜在临床应用价值。