Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis
Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis
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DOI：
10.1073/pnas.0607242103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Hemmer, Bernhard
中科院分区：
文献类型：
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作者：
Zhou, Dun;Srivastava, Rajneesh;Hemmer, Bernhard
多发性硬化（MS）是中枢神经系统的慢性炎症性疾病。虽然MS的原因仍然不确定，但许多发现指向对髓鞘抗原的持续自身免疫反应。髓鞘少突胶质细胞糖蛋白（MOG）位于髓鞘外表面，在实验性自身免疫性脑脊髓炎模型中具有致病性，是MS潜在的致病性自身抗原之一。在这项研究中，我们解决了自身抗体的发生，以本地MOG和它的含义脱髓鞘和轴突损失在MS。我们采用了高灵敏度的生物测定，它允许检测自身抗体结合到细胞外部分的本地MOG。抗体，主要是IgG，在血清中发现，具有高亲和力的MOG的胞外结构域的严格构象表位结合。与不同的对照组相比，MS患者中天然MOG的IgG而非IgM抗体滴度显著较高，其中原发性进展性MS患者的患病率最高。天然MOG的血清自身抗体在体外诱导表达MOG的靶细胞死亡。来自具有高抗MOG抗体滴度的MS患者的血清染色大鼠脑中的白色物质髓鞘，并且当转移到自身免疫性脑脊髓炎动物时增强脱髓鞘和轴突损伤。总体而言，这些发现表明MS患者亚组中对天然MOG的致病性抗体应答。
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Although the cause of MS is still uncertain, many findings point toward an ongoing autoimmune response to myelin antigens. Because of its location on the outer surface of the myelin sheath and its pathogenicity in the experimental autoimmune encephalomyelitis model, myelin oligodendrocyte glycoprotein (MOG) is one of the potential disease-causing self antigens in MS. However, the role of MOG in the pathogenesis of MS has remained controversial. In this study we addressed the occurrence of autoantibodies to native MOG and its implication for demyelination and axonal loss in MS. We applied a high-sensitivity bioassay, which allowed detecting autoantibodies that bind to the extracellular part of native MOG. Antibodies, mostly IgG, were found in sera that bound with high affinity to strictly conformational epitopes of the extracellular domain of MOG. IgG but not IgM antibody titers to native MOG were significantly higher in MS patients compared with different control groups with the highest prevalence in primary progressive MS patients. Serum autoantibodies to native MOG induced death of MOG-expressing target cells in vitro. Serum from MS patients with high anti-MOG antibody titers stained white matter myelin in rat brain and enhanced demyelination and axonal damage when transferred to autoimmune encephalomyelitis animals. Overall these findings suggest a pathogenic antibody response to native MOG in a subgroup of MS patients.