Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity.
Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity.
复制标题
DOI：
10.3389/fnins.2021.649876
复制
发表时间：
2021
影响因子：
4.3
通讯作者：
Bielekova B
中科院分区：
文献类型：
--
作者：
Masvekar R;Phillips J;Komori M;Wu T;Bielekova B
多发性硬化症 (MS) 相关炎症可分为病变活动（由从外周迁移到中枢神经系统 (CNS) 的免疫细胞介导）和非病变活动（由划分到 CNS 组织的炎症介导）。磁共振成像 (MRI) 上的对比增强病变 (CEL) 反映的病变炎症活动可被当前的疾病修饰疗法 (DMT) 有效抑制。然而，DMT 对非病变炎症活动的影响目前尚不清楚。必须同时可靠地测量病变和非病变 MS 活性，以了解它们对个体患者中枢神经系统组织破坏的贡献。我们之前证明，中枢神经系统区室化炎症可以通过脑脊液（CSF）免疫细胞和细胞特异性可溶性标记物的联合定量来测量。本研究的目的是开发和验证基于脑脊液生物标志物的多发性硬化症病变活动的分子替代物。训练队列分为活跃组（CEL > 1 或临床复发）和非活动病变活动组（无 CEL 或复发）。以盲法方式分析匹配的脑脊液和血清样本中的 20 种炎症和轴突损伤生物标志物。仅假阳性概率低于 0.1%（即 p < 0.001）的训练队列的结果在独立验证队列中得到验证。具有病变活动性的多发性硬化症患者的 IL-12p40、CHI3L1、TNFα、TNFβ 和 IL-10 升高，其中前两者具有最强的作用，并在独立验证队列中验证了与病变活动性的统计显着相关性。在具有活动性病变的多发性硬化症患者中，在脑脊液 (cNfL) 中测量的轴突损伤标志物神经丝光 (NfL) 也显着升高。尽管 cCSF 和 sNfL 相关（Rho = 0.66，p < 0.0001），但血清中测量的 NfL (sNfL) 并未以预定的显着性区分两个 MS 亚组 (p = 0.0690)。最后，IL12p40 和 CHI3L1 的加性模型优于任何生物标志物。主要由髓系免疫细胞释放的 IL12p40 和 CHI3L1 是 MS 病变活动的最佳 CSF 生物标志物。 IL12p40/CHI3L1-cNfL 相关性的残差可以识别具有更具破坏性炎症或导致神经变性的多发性硬化症患者。
Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.
登录
查看更多内容
脑脊液标记物显示出进行性多发性硬化症的鞘内炎症。
影响因子：
11.2
作者：
Komori M;Blake A;Greenwood M;Lin YC;Kosa P;Ghazali D;Winokur P;Natrajan M;Wuest SC;Romm E;Panackal AA;Williamson PR;Wu T;Bielekova B
通讯作者：
Bielekova B
影响因子：
--
作者：
Hernández-Pedro NY;Espinosa-Ramirez G;de la Cruz VP;Pineda B;Sotelo J
通讯作者：
Sotelo J
影响因子：
9.3
作者：
Bonneh-Barkay D;Wang G;Starkey A;Hamilton RL;Wiley CA
通讯作者：
Wiley CA
影响因子：
14.5
作者：
Comabella, Manuel;Fernandez, Marta;Montalban, Xavier
通讯作者：
Montalban, Xavier
影响因子：
4
作者：
Kosa, Peter;Komori, Mika;Bielekova, Bibiana
通讯作者：
Bielekova, Bibiana