Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.
Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.
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DOI：
10.1212/nxi.0000000000200099
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发表时间：
2023-05
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脊髓损伤 (SCI) 会破坏中枢神经系统和免疫系统之间的精细平衡相互作用，并可能导致适应不良的异常免疫反应。该研究检查了 SCI 后新出现的自身抗体合成，与位于完整神经元膜上的构象脊髓表位和表面肽的结合。这是一项在急性护理和住院康复中心进行的前瞻性纵向队列研究，并结合对档案组织样本进行的神经病理学病例对照研究，范围从急性损伤（基线）到损伤后几个月（随访）。在队列研究中，使用基于组织的测定（TBA）和背根神经节（DRG）神经元培养物以盲法检查血清自身抗体结合。比较了创伤性运动性完全性 SCI 组、运动性不完全性 SCI 组和孤立性椎体骨折（无 SCI）组（对照组）。在神经病理学研究中，通过将 SCI 与神经病理学未改变的脊髓组织进行比较，检查脊髓病变部位的 B 细胞浸润和抗体合成。此外，还对个别患者的脑脊液进行了探索。 TBA 和 DRG 评估中出现的自身抗体结合仅限于 SCI 患者亚群（16%，9/55 血清），而在椎骨骨折对照中不存在（0%，0/19 血清）。与脊髓结合的自身抗体特征性地检测到了胶质质，这是一个参与感觉运动整合和疼痛处理的高突触密度的少髓鞘区域。自身抗体结合在运动性完全性 SCI 后最为频繁（美国脊髓损伤协会损伤量表 A/B 级，22%，8/37 血清），并且与神经性止痛药物相关。同时，神经病理学研究表明，27% (6/22) 的 SCI 患者病变脊髓存在 B 细胞 (CD20、CD79a) 浸润，9% (2/22) 存在浆细胞 (CD138)。 IgG 和 IgM 抗体合成共定位于活化补体 (C9neo) 沉积区域。对另一名患者的纵向脑脊液分析表明，随着血脊髓屏障的重新开放，鞘内抗体从头合成（IgM）出现。这项研究为对神经病理性止痛药物有高需求的患者亚群在 SCI 后约 3 周出现的抗体介导的自身免疫反应提供了免疫学、神经生物学和神经病理学的原理验证。针对特定脊髓和神经元表位的新兴自身免疫表明存在创伤性中枢神经系统自身免疫综合征。
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.