Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals
Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals
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DOI：
10.1073/pnas.0901496106
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发表时间：
2009-05-19
影响因子：
11.1
通讯作者：
Meinl, Edgar
中科院分区：
文献类型：
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作者：
Derfuss, Tobias;Parikh, Khyati;Meinl, Edgar
灰质病理学越来越被认为是多发性硬化症 (MS) 的一个重要特征，但针对灰质的免疫反应的性质却知之甚少。从蛋白质组学方法开始，我们确定了 contactin-2/瞬时表达的轴突糖蛋白 1 (TAG-1) 作为候选自身抗原，可被多发性硬化症患者的自身抗体和 T 辅助 (Th) 1/Th17 T 细胞识别。 Contactin-2 及其大鼠同源物 TAG-1 由各种神经元群表达，并隔离在轴突和髓磷脂侧有髓轴突的近节旁结构域中。然后在大鼠实验性自身免疫性脑炎模型中探讨了这些自身免疫反应的致病意义。 TAG-1 特异性 T 细胞的过继转移诱发脑炎，其特征是脊髓和皮质灰质优先发生炎症。 TAG-1 特异性 T 细胞与髓鞘少突胶质细胞糖蛋白特异性 mAb 的共转移在皮质中产生局灶性血管周围脱髓鞘病变，并在脊髓灰质和白质中产生广泛脱髓鞘。这项研究将 contactin-2 确定为 MS 中 T 细胞和自身抗体靶向的自身抗原。我们的研究结果表明，contactin-2 特异性 T 细胞反应有助于灰质病理学的发展。
Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1-specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1-specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2-specific T-cell response contributes to the development of gray matter pathology.