From the The Belford Center for Spinal Cord Injury (J.M.S., P.G.P.), The Ohio State University, Wexner Medical Center, Columbus; Departments of Neurology (J.M.S.), Physical Medicine and Rehabilitation, and Neurosciences, The Ohio State University, Columbus; Department of Neurology and Experimental Neurology (J.M.S., M.A.K., T. Liebscher, T. Lübstorf, C.B., L.S.-N., U.D., H.P.), Spinal Cord Injury Research (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Division of Neuropathology and Neurochemistry (C.H., V.E., G.R., R.H.), Department of Neurology, Medical University of Vienna, Austria; Department of Neurology (T.Z.), Medical University of Vienna, Austria; Department of Neurophysiology and Neuropharmacology (Center for Physiology and Pharmacology) (H.K.), Medical University of Vienna, Austria; Department of Orthopaedics and Trauma Surgery (T.H.), Medical University of Vienna, Austria; Treatment Centre for Spinal Cord Injuries (Thomas Liebscher), BG Hospital Unfallkrankenhaus Berlin, Germany; Spinal Cord Injury Center (A.C.), Balgrist University Hospital, Zurich, Switzerland; Division of Trauma Surgery (P.C.), University Hospital Zürich, Switzerland; IRCCS Fondazione S. Lucia (G.S.), Spinal Cord Unit, Rome, Italy; Division of Neurosurgery and Spine Program (M.G.F.), University of Toronto, ON, Canada; Ruhr-University Bochum (C. May, A.G., K.M.), Center for Protein Diagnostics (PRODI), Medical Proteome Center, Universitätsstraße 150, Bochum, Germany; Institute of Medical Immunology (C. Meisel), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Immunology (C. Meisel), Labor Berlin-Charité Vivantes GmbH, Germany; Berlin Institute of Health (U.D.), QUEST-Center for Transforming Biomedical Research, Germany; Department of Clinical Epidemiology and Applied Biostatistics (P.M.), Eberhard Karls Universität Tübingen, Germany; Department of Neurosciences (P.G.P.), The Ohio State University, Columbus; and Center for Brain Research (H.L.), Medical University of Vienna, Austria; Comprehensive Center for Clinical Neurosciences and Mental Health (C.H., T.Z., V.E., G.R., R.H.), Medical University of Vienna, Austria.
Neurol Neuroimmunol Neuroinflamm. 2023 Apr 5;10(3). doi: 10.1212/NXI.0000000000200099. Print 2023 May.
Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane.
This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored.
Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier.
This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.
脊髓损伤（SCI）破坏了中枢神经系统和免疫系统之间的精细平衡互作，可导致适应性异常免疫反应。本研究旨在探究 SCI 后与构象性脊髓表位和完整神经元膜表面肽结合的新型自身抗体的合成。
这是一项前瞻性纵向队列研究，在急性护理和住院康复中心进行，并结合存档组织样本的神经病理学病例对照研究，时间范围从急性损伤（基线）到之后的几个月（随访）。在队列研究中，采用组织为基础的检测（TBA）和背根神经节（DRG）神经元培养，以盲法检测血清自身抗体结合情况。将创伤性运动完全性 SCI 组、运动不完全性 SCI 组和无 SCI 的单纯椎体骨折组（对照组）进行比较。在神经病理学研究中，通过比较 SCI 与神经病理学未改变的脊髓组织，研究脊髓损伤部位的 B 细胞浸润和抗体合成。此外，还对单个患者的 CSF 进行了探索。
只有在 SCI 患者亚群中才检测到新型自身抗体结合（16%，55 份血清中的 9 份），而在椎体骨折对照组中则未检测到（0%，19 份血清中无）。针对脊髓的自身抗体结合特征性地检测到了胶状质，这是一个少突胶质细胞的区域，突触密度高，参与感觉运动整合和疼痛处理。在运动完全性 SCI 后（美国脊髓损伤协会损伤分级 A/B 级，22%，37 份血清中的 8 份），自身抗体结合最常见，且与神经病理性疼痛药物有关。同时，神经病理学研究显示，27%（22 例患者中的 6 例）的 SCI 患者存在脊髓损伤部位的 B 细胞浸润（CD20、CD79a），9%（22 例患者中的 2 例）存在浆细胞（CD138）。IgG 和 IgM 抗体合成与激活补体（C9neo）沉积区域共定位。对另一位单一患者的纵向 CSF 分析显示，在具有较高神经病理性疼痛药物需求的患者亚群中，大约在 SCI 后 3 周出现新型（IgM）鞘内抗体合成。
本研究提供了免疫、神经生物学和神经病理学方面的初步证据，证明在具有较高神经病理性疼痛药物需求的患者亚群中，大约在 SCI 后 3 周出现针对特定脊髓和神经元表位的抗体介导自身免疫反应。针对特定脊髓和神经元表位的新型自身抗体提示存在创伤后中枢神经系统自身免疫综合征。
