Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein
Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein
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DOI：
10.1002/ana.25291
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发表时间：
2018-08-01
影响因子：
11.2
通讯作者：
Meinl, Edgar
中科院分区：
文献类型：
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作者：
Spadaro, Melania;Winklmeier, Stephan;Meinl, Edgar
目的抗髓鞘少突胶质细胞糖蛋白(MOG)自身抗体存在于部分中枢神经系统炎性脱髓鞘疾病患者中。我们通过亲和纯化患者的抗体(Abs)并将其转移到实验动物身上来分析它们的致病活性。方法采用细胞鉴定方法对抗MOG抗体的患者进行鉴定。我们确定了与啮齿动物MOG的交叉反应和识别的MOG表位。我们从患者的血液中制备了正确折叠的MOG胞外区和亲和纯化的MOG特异性抗体。用纯化的抗体对中枢神经系统组织进行染色，并转移到两种实验性自身免疫性脑脊髓炎模型中。结果我们从我们的门诊确诊了17例MOG抗体患者，其中2例对啮齿动物MOG有交叉反应；两人都有反复发作性视神经炎。亲和纯化的抗体识别转基因细胞上的MOG，并在组织切片上染色髓鞘。这2例患者的抗体识别MOG、CC和FG环上的不同表位。在我们2-3年的观察期内，这两个病人的抗体都持续存在。在两种不同的大鼠模型鞘内注射时，两种患者的抗MOG抗体均具有致病性。这些抗体与同源的MOG特异性T细胞一起，增强了T细胞的渗透；与髓鞘碱性蛋白特异性T细胞一起，它们诱导了与C9neo沉积相关的脱髓鞘，类似于II型多发性硬化症的病理。解释从炎症性脱髓鞘疾病患者中纯化的MOG特异性抗体与髓鞘反应性T细胞共转移时会在体内诱导病理变化，表明这些抗体在患者中具有类似的致病性。Ann Neurol 2018；84：315-328
ObjectiveAutoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed their pathogenic activity by affinity-purifying these antibodies (Abs) from patients and transferring them to experimental animals.MethodsPatients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically.ResultsWe identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T-cell infiltration; together with myelin basic protein-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology.InterpretationMOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315-328