Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants
Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants
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DOI：
10.1007/s00401-015-1500-6
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发表时间：
2015-12-01
影响因子：
12.7
通讯作者：
Owens, Gregory P.
中科院分区：
文献类型：
--
作者：
Blauth, Kevin;Soltys, John;Owens, Gregory P.
B细胞与多发性硬化（MS）的病因学有关。鞘内IgG合成，脑脊液（CSF）寡克隆带和病变IgG沉积表明抗体介导的病理作用。我们检测了来自MS患者CSF扩增的B细胞克隆的IgG 1单克隆重组抗体（rAb）与中枢神经系统（CNS）组织的结合。进一步测试了展示CNS与小鼠和人CNS组织结合的MS rAb在离体脊髓外植体培养物中诱导补体介导的组织损伤的能力。CNS组织、原代人星形胶质细胞和人神经元的染色显示MS rAb与星形胶质细胞和神经元上优先表达的抗原结合的可测量偏倚。很少检测到识别髓鞘富集抗原的MS rAb。髓鞘特异性和一些星形胶质细胞/神经元特异性MS rAbs在补体存在下应用于脊髓外植体培养物时引起显著的髓鞘损失和星形胶质细胞活化。总体而言，多发性硬化症中鞘内B细胞反应与神经胶质和神经元靶点结合，并在脊髓外植体培养物中产生脱髓鞘，表明鞘内IgG参与MS发病机制。
B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.