From the Servei de Neurologia-Neuroimmunologia (N.F., C.M.-B., C.C., R.P., V.B., X.M., M.C.L.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; Biotech Research and Innovation Centre (BRIC) (M.O., S.I.-N.), University of Copenhagen, Denmark; Statistics and Bioinformatics Unit (B.M., A.S.), Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain; Genetics, Microbiology and Statistics Department (A.S.), Universitat de Barcelona, Spain; Department of Neurology (I.D.), University of Belgrade School of Medicine, Serbia; Department of Neurology (I.D.), University of North Carolina School of Medicine, Chapel Hill; Department of Neurology (M.V., M.K.), Medical University of Graz, Austria; Proteomics Unit (E.B., E.S.), Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), Spain; Proteomics Unit (E.B., E.S.), Universitat Pompeu Fabra, Barcelona, Spain; and Center for Multiple Sclerosis (X.M.), St. Michael's Hospital, University of Toronto, ON, Canada.
Neurol Neuroimmunol Neuroinflamm. 2021 Jan 12;8(2). doi: 10.1212/NXI.0000000000000941. Print 2021 Mar.
To identify biomarkers associated with progressive phases of MS and with neuroprotective potential.
Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).
Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, = 0.02) and NINCs (1,617 vs 838.6 ng/mL, = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, = 0.01).
These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.
鉴定与多发性硬化症（MS）进展阶段和神经保护潜能相关的生物标志物。
综合分析实验性自身免疫性脑脊髓炎（EAE）慢性进展期中枢神经系统组织的转录组和蛋白质组谱，以及鼠神经干细胞向神经元分化过程中的转录组谱。通过 ELISA 测量 65 例 MS 患者（29 例复发缓解型 MS [RRMS]、20 例继发进展型 MS 和 16 例原发进展型 MS [PPMS]）和 30 例非炎症性神经学对照（NINCs）脑脊液中的候选生物标志物。
基因和蛋白质表达数据的综合分析鉴定出 2 个生物标志物，即丝氨酸蛋白酶抑制剂 Serpina3n 和钙结合蛋白 S100A4，它们在慢性进展性 EAE 中上调，其表达在神经元分化过程中被诱导。免疫荧光研究显示，S100A4 和 Serpina3n 在 EAE 期间主要表达于神经元。与 NINCs 相比，MS 患者脑脊液中 SERPINA3（人 Serpina3n 的同源物）和 S100A4 的水平升高（SERPINA3：1320 与 838.6ng/ml， = 0.0001；S100A4：1.6 与 0.8ng/ml， = 0.02）。在 MS 组中，与 RRMS 患者相比，进展型患者，特别是 PPMS 患者，CSF SERPINA3 水平显著升高（1617 与 1129ng/ml， = 0.02）和 NINCs（1617 与 838.6ng/ml， = 0.0001）。有趣的是，只有在 PPMS 组中，CSF SERPINA3 水平与 CSF 神经丝轻链水平显著相关（r = 0.62， = 0.01）。
这些结果表明 SERPINA3 作为与 MS 进展形式相关的生物标志物的作用，特别是 PPMS。
