Human lupus autoantibodies against NMDA receptors mediate cognitive impairment

被引:276
作者
Kowal, Czeslawa
DeGiorgio, Lorraine A.
Lee, Ji Y.
Edgar, Mark A.
Huerta, Patricio T.
Volpe, Bruce T.
Diamond, Betty
机构
[1] Columbia Univ, Ctr Med, Dept Med, New York, NY 10032 USA
[2] Cornell Univ, Joan & Stanford I Weill Med Coll, Burke Med Res Inst, Dept Neurol & Neurosci, White Plains, NY 10605 USA
[3] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
关键词
brain-derived antibodies; neuropsychiatric systemic lupus erythematosus; neurotoxic antibodies;
D O I
10.1073/pnas.0608397104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:19854 / 19859
页数:6
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