Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice
Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice
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DOI：
10.1093/brain/awp309
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发表时间：
2010-02-01
期刊：
影响因子：
14.5
通讯作者：
Papadopoulos, Marios C.
中科院分区：
文献类型：
--
作者：
Saadoun, Samira;Waters, Patrick;Papadopoulos, Marios C.
视神经脊髓炎是一种中枢神经系统炎症性脱髓鞘疾病，与神经胶质水通道蛋白水通道蛋白 4 的自身抗体有关。最近有报道称，外周注射来自视神经脊髓炎患者的免疫球蛋白不会引起幼稚大鼠的病变，但仅当存在预先存在的中枢神经系统炎症时才会引起病变。在此，我们研究了来自水通道蛋白 4 自身抗体阳性视神经脊髓炎患者的免疫球蛋白 G 是否有可能单独或在人补体存在下损害中枢神经系统。来自视神经脊髓炎患者的免疫球蛋白 G 不会激活小鼠补体，并且在注射到小鼠大脑中时不具有致病性。然而，将视神经脊髓炎患者的免疫球蛋白 G 与人补体共同注射，在小鼠体内产生了类似视神经脊髓炎的病变。在联合注射视神经脊髓炎患者的免疫球蛋白 G 和人补体后 12 小时内，水通道蛋白 4 表达显着下降，胶质细胞水肿，髓鞘质破坏和轴突损伤，但实质内炎症很少。 7 天时，出现广泛的炎症细胞浸润、活化补体成分的血管周围沉积、广泛脱髓鞘、水通道蛋白 4 表达丧失、反应性星形胶质细胞丧失和神经元细胞死亡。在行为研究中，将视神经脊髓炎患者的免疫球蛋白 G 和人类补体注射到右半球的小鼠在 7 天时优先转向右侧。在接受来自非视神经脊髓炎患者的免疫球G和人补体的野生型小鼠中，或在接受来自视神经脊髓炎患者的免疫球蛋白G和人补体的水通道蛋白4缺失小鼠中，没有观察到脑炎症、脱髓鞘或右转行为。我们的结论是，视神经脊髓炎患者的免疫球蛋白 G 与人补体共注射再现了视神经脊髓炎的关键组织学特征，并且水通道蛋白 4 对于视神经脊髓炎患者的免疫球蛋白 G 发挥其作用是必要且充分的。在我们的小鼠模型中，来自视神经脊髓炎患者的免疫球蛋白 G 不需要预先存在的中枢神经系统炎症来产生病变。
Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.