Neuron-binding human monoclonal antibodies support central nervous system neurite extension
Neuron-binding human monoclonal antibodies support central nervous system neurite extension
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DOI：
10.1093/jnen/63.5.461
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发表时间：
2004-05-01
影响因子：
3.2
通讯作者：
Rodriguez, M
中科院分区：
文献类型：
--
作者：
Warrington, AE;Bieber, AJ;Rodriguez, M
两种人免疫球蛋白(sHIgM12和sHIgM42)在体外支持中枢神经系统(CNS)神经突起的延伸，相当于强大的神经突起刺激分子层粘连蛋白。这两种免疫球蛋白在未固定的中枢神经系统组织中与多种细胞类型结合，在培养中与神经元表面结合。两种单抗均可阻断中枢神经系统小鼠髓鞘对颗粒细胞突起生长的抑制作用。MAb既不与成熟少突胶质细胞表面结合，也不与髓鞘蛋白严格共定位。唾液酸酶处理消除了这两种单抗的神经元表面结合，而用伏马菌素B阻断鞘磷脂的合成，或用PIPLC去除GPI连接的蛋白不能。当sHIgM12和sHIgM42用作混合神经元/神经胶质集合体的底物时，它们支持强大的轴突延伸，而星形胶质细胞仍留在聚集体中。相反，层粘连蛋白支持星形胶质细胞的迁移和扩散。支持轴突延伸的人类单抗是一种新的因子，可用于鼓励损伤后的轴突修复，同时最大限度地减少神经胶质细胞的渗透。这两种人单抗都是从单克隆性丙种球蛋白病患者身上分离出来的。每个人在循环中携带高滴度的mAb已有数年之久，没有受到损害。因此，sHIgM12和sHIgM42不太可能是系统性致病的。
Two human IgMs (sHIgM12 and sHIgM42) were identified that supported in vitro central nervous system (CNS) neurite extension equal to the potent neurite stimulatory molecule laminin. Both IgMs bound to multiple cell types in unfixed CNS tissue and to the surface of neurons in culture. Both monoclonal antibodies (mAbs) overrode the inhibitory effect of CNS mouse myelin on granule cell neurite extension. Neither mAb bound to the surface of mature oligodendrocytes or strictly colocalized with myelin proteins. Sialidase treatment eliminated the neuronal surface binding of both mAbs, whereas blocking sphingolipid synthesis with Fumonisin B, or removing GPI-linked proteins with PIPLC did not. When used as substrates for mixed neuron/glia aggregates, sHIgM12 and sHIgM42 supported robust neurite extension while astrocytes remained in the aggregates. In contrast, laminin supported astrocyte migration and spreading. Human mAbs that support neurite extension are novel factors that may be of use in encouraging axon repair following injury while minimizing glial cell infiltration. Both human mAbs were isolated from individuals with monoclonal gammopathy. Each individual has carried high mAb titers in circulation for years without detriment. sHIgM12 and sHIgM42 are therefore unlikely to be systemically pathogenic.