Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis
Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis
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DOI：
10.1073/pnas.0510672103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Genain, CP
中科院分区：
文献类型：
--
作者：
Lalive, PH;Menge, T;Genain, CP
髓磷脂少突胶质细胞糖蛋白 (MOG) 是中枢神经系统少突胶质细胞和最外层髓磷脂层中表达的整合膜蛋白。抗 MOG 抗体会导致多发性硬化症 (MS) 动物模型中的髓磷脂破坏（脱髓鞘）；然而，此类致病性抗体尚未在人类中得到表征。在此，使用一种特异性检测 IgG 与 MOG 转染的哺乳动物细胞上天然膜嵌入构象中的人 MOG 结合的方法来评估这些自身抗体的重要性。与健康对照相比，天然 MOG 特异性 IgG 最常见于临床孤立综合征 (P < 0.001) 和复发缓解型 MS (P < 0.01) 的血清中，仅在继发进展型 MS 中少量出现 (P < 0.05)，而在原发进展型 MS 中根本不存在。我们证明，在这种基于细胞的测定中暴露的表位与通过固相 ELISA 测试的人重组 MOG 的重折叠胞外结构域上暴露的表位不同。在诱导发生 MS 样中枢神经系统炎性脱髓鞘的狨猴中，与针对其他髓磷脂成分的反应不同，在疾病临床发作之前总是检测到针对天然膜结合 MOG 的 IgG 反应性 (P < 0.0001)。我们的结论是：(i) 体内表达的天然糖基化 MOG 上展示的表位是致病性抗体的早期靶标； (h) 这些在固相测定中未检测到的抗体可能在具有主要炎症活性的早期多发性硬化症中发挥致病作用； (iii)基于细胞的测定为中枢神经系统自身免疫性脱髓鞘的早期检测提供了实用的血清学标记，包括至少在灵长类MS模型中的临床前阶段。
Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demyelination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here,a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these auto Abs. Compared with healthy controls, native MOG-specific IgGs were most frequently found in serum of clinically isolated syndromes (P < 0.001) and relapsing-remitting MS (P < 0.01), only marginally in secondary progressive MS (P < 0.05), and not at all in primary progressive MS. We demonstrate that epitopes exposed in this cell-based assay are different from those exposed on the refolded, extracellular domain of human recombinant MOG tested by solid-phase ELISA. In marmoset monkeys induced to develop MS-like CNS inflammatory demyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other myelin constituents. We conclude that (i) epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs; (h) these Abs, which are not detected in solid-phase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and (iii) the cell-based assay provides a practical serologic marker for early detection of CNS autoimmune demyelination including its preclinical stage at least in the primate MS model.