Human lupus autoantibodies against NMDA receptors mediate cognitive impairment
Human lupus autoantibodies against NMDA receptors mediate cognitive impairment
复制标题
DOI：
10.1073/pnas.0608397104
复制
发表时间：
2006-12-26
影响因子：
11.1
通讯作者：
Diamond, Betty
中科院分区：
文献类型：
--
作者：
Kowal, Czeslawa;DeGiorgio, Lorraine A.;Diamond, Betty
神经精神系统性红斑狼疮，这往往会导致认知障碍和记忆丧失，已成为狼疮患者的主要并发症。以前，我们开发了一个神经精神性狼疮的小鼠模型的基础上的抗体与双链DNA和NMDA受体（NMDAR）的交叉反应。我们表明，这些小鼠抗体损害认知时，他们通过在血脑屏障（BBB）的突破触发脂多糖进入中枢神经系统。由于研究表明狼疮患者的血清和脑脊液中含有抗NMDAR抗体，因此我们决定研究这些人类抗体是否有助于认知功能障碍。在这里，我们表明，从狼疮患者中提取的血清与DNA和NMDAR的反应性引起小鼠的认知功能障碍，静脉注射血清，并给予脂多糖损害BBB的完整性。脑组织病理学显示海马神经元损伤，行为学测试显示海马依赖性记忆障碍。为了确定抗NMDAR Ab是否存在于系统性红斑狼疮患者的脑中，我们从患者的脑中洗脱IgG。当注射到小鼠脑中时，IgG结合DNA和NMDAR并引起神经元凋亡。我们检查了另外四名患有神经精神性狼疮的患者的大脑，发现它们显示出与抗NMDAR抗体共定位的内源性IgG。我们的研究结果表明，狼疮患者具有循环的抗NMDAR抗体，如果它们破坏BBB，则能够引起神经元损伤和记忆缺陷，并且抗体存在于患者的大脑中。神经精神狼疮的哪些方面可能由抗NMDAR抗体介导，频率如何，以及哪些患者现在是重要的临床问题。
Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharicle to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.