The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice
The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice
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DOI：
10.1172/jci37338
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Willison, Hugh J.
中科院分区：
文献类型：
--
作者：
Greenshields, Kay N.;Halstead, Susan K.;Willison, Hugh J.
抗GM1神经节苷脂自身抗体被用作运动轴索周围神经病的诊断标志物，并且被认为是此类疾病的主要介质。然而，它们在神经元膜上结合和发挥致病作用的能力是高度不一致的。使用人类和小鼠的单克隆抗GM1抗体探测GM1丰富的运动神经末梢膜在小鼠中，我们在这里表明，GM1的抗原性寡糖在活质膜是隐蔽的，隐藏在表面域，成为埋葬的一部分抗GM1抗体由于掩蔽效应的邻近神经节苷脂。通过唾液酸酶处理，从掩蔽的神经节苷脂（包括GD1a）中释放唾液酸，或通过冷冻或固定破坏五种膜，暴露隐藏的GM1结合结构域。这种隐蔽的行为也在固相免疫测定中重现。这些数据表明，某些抗GM1抗体发挥有效的补体激活介导的神经致病作用，包括在活的末端运动轴突的形态学损伤，导致突触传递的阻断。这只发生在GM1拓扑上可用于抗体结合时，而不是当GM1是隐蔽的。神经节苷脂膜拓扑结构的复杂性的这一修订的理解提供了一个机制帐户的抗GM1抗体的神经病变潜力的广泛变化。
Anti-GM1 anglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the five membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.