Furlan Roberto, Schaedelin Sabine, Frederiksen Jette Lautrup, Watanabe Mitsuru, Piehl Fredrik, Fink Katharina, Iacobaeus Ellen, Evertsson Björn, Khademi Mohsen, Gastaldi Matteo, Greco Giacomo, Mariotto Sara, Carta Sara, Di Sapio Alessia, Bava Cecilia Irene, Giorgi Lucia, Benkert Pascal, Maceski Aleksandra Maleska, Oechtering Johanna, Willemse Eline, Pröbstel Anne-Katrin, Pretzsch Roxanne, Finardi Annamaria, Mandelli Alessandra, Anthony Daniel, Kuhle Jens, Leppert David
Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS Ospedale San Raffaele, and Vita e Salute San Raffaele University, 20132 Milan, Italy.
Department of Clinical Research, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
Brain. 2025 Sep 24. doi: 10.1093/brain/awaf345.
Granulocytes play a well-established role in the pathogenesis of brain tissue damage in neuromyelitis optica spectrum disorder (NMOSD). The release of granulocyte activation markers (GAM) into CSF has recently been shown to distinguish NMOSD from multiple sclerosis (MS) with high accuracy. However, their pathogenetic role in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear, and their usefulness for diagnostic differentiation is unknown. This observational cohort study by eight tertiary centres in Europe and Japan included 244 CSF samples from patients with MOGAD (n=71), NMOSD (n=48), MS (n=125), and control persons (n=19). CSF levels of GAM (neutrophil elastase, myeloperoxidase, NGAL, MMP-8, MMP-9), astrocyte damage markers (ADM: glial fibrillary acidic protein (GFAP), S100B), and complement factors C5 and C5a were analysed by capillary ELISA (Ella™) or Luminex®. The primary outcome was the capacity of these markers to differentiate MOGAD, NMOSD, and MS in the acute (≤21 days post-exacerbation) stage, and the correlation of GAM with C5 and C5a. Secondary analyses included the correlations of these markers with disability severity, measured by the Expanded Disability Status Scale (EDSS). GAM (except for MMP-9), ADM, and C5/C5a levels peaked at onset of disease exacerbation of MOGAD and NMOSD (regardless of aquaporin-4 antibody status), and were significantly higher than in MS. MMP-9 levels were continuously increased in MS over MOGAD and NMOSD, both in acute and subacute/chronic stages. C5 and C5a were equally increased over MS in acute stages of MOGAD and NMOSD. A logistic model and receiver operating characteristics analyses incorporating GAM and C5 displayed high discriminatory power between MOGAD/NMOSD vs MS (area under the curve (AUC) 0.880), NMOSD vs MS (AUC 0.837), and MOGAD vs MS (AUC 0.925) in acute stages. Accordingly, increased ADM levels in NMOSD differentiated NMOSD from MS and MOGAD (AUC 0.897 and 0.843, respectively). GAM levels correlated with EDSS scores in MOGAD and NMOSD, but not in MS, while those of ADM correlated with disability in NMOSD, but not in MOGAD and MS. Determining CSF levels of GAM and C5/C5a, and of ADM provide a biology-driven approach to differentiate MOGAD, NMOSD and MS. Their measurement can be processed faster and with similar accuracy than with most auto-antibody assays, enabling timely initiation of appropriate therapy in acute presentations. The correlation between GAM and C5/C5a levels with neurological impairment in MOGAD and NMOSD corroborates their role as effectors of neural damage, supporting the acute stage use of inhibitors of C5 activation.
粒细胞在视神经脊髓炎谱系障碍（NMOSD）的脑组织损伤发病机制中发挥着公认的作用。最近研究表明，粒细胞激活标志物（GAM）释放到脑脊液中能够高度准确地区分NMOSD和多发性硬化症（MS）。然而，它们在髓鞘少突胶质细胞糖蛋白抗体相关疾病（MOGAD）中的致病作用尚不清楚，其在诊断鉴别中的作用也未知。这项由欧洲和日本八个三级中心开展的观察性队列研究纳入了来自MOGAD患者（n = 71）、NMOSD患者（n = 48）、MS患者（n = 125）和对照者（n = 19）的244份脑脊液样本。通过毛细管酶联免疫吸附测定（Ella™）或Luminex®分析脑脊液中GAM（中性粒细胞弹性蛋白酶、髓过氧化物酶、中性粒细胞明胶酶相关脂质运载蛋白、基质金属蛋白酶-8、基质金属蛋白酶-9）、星形胶质细胞损伤标志物（ADM：胶质纤维酸性蛋白（GFAP）、S100B）以及补体因子C5和C5a的水平。主要研究结果是这些标志物在急性期（疾病加重后≤21天）区分MOGAD、NMOSD和MS的能力，以及GAM与C5和C5a的相关性。次要分析包括这些标志物与通过扩展残疾状态量表（EDSS）测量的残疾严重程度的相关性。MOGAD和NMOSD（无论水通道蛋白-4抗体状态如何）疾病加重发作时，GAM（MMP-9除外）、ADM以及C5/C5a水平达到峰值，且显著高于MS。在急性期和亚急性/慢性期，MS中的MMP-9水平均持续高于MOGAD和NMOSD。在MOGAD和NMOSD的急性期，C5和C5a相对于MS同样升高。纳入GAM和C5的逻辑模型及受试者工作特征分析显示，在急性期，MOGAD/NMOSD与MS之间（曲线下面积（AUC）为0.880）、NMOSD与MS之间（AUC为0.837）以及MOGAD与MS之间（AUC为0.925）具有较高的鉴别力。因此，NMOSD中升高的ADM水平可将NMOSD与MS和MOGAD区分开来（AUC分别为0.897和0.843）。GAM水平与MOGAD和NMOSD中的EDSS评分相关，但与MS中的无关，而ADM水平与NMOSD中的残疾相关，但与MOGAD和MS中的无关。测定脑脊液中GAM、C5/C5a以及ADM的水平为区分MOGAD、NMOSD和MS提供了一种基于生物学的方法。与大多数自身抗体检测相比，它们的检测速度更快且准确性相似，能够在急性发作时及时启动适当的治疗。MOGAD和NMOSD中GAM和C5/C5a水平与神经功能损害之间的相关性证实了它们作为神经损伤效应器的作用，支持在急性期使用C5激活抑制剂。
