Kowal Czeslawa, DeGiorgio Lorraine A, Nakaoka Tsukasa, Hetherington Hoby, Huerta Patricio T, Diamond Betty, Volpe Bruce T
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Immunity. 2004 Aug;21(2):179-88. doi: 10.1016/j.immuni.2004.07.011.
Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.
狼疮(系统性红斑狼疮,SLE)患者会出现进行性认知丧失,而无中枢神经系统血管疾病或炎症的证据。SLE患者产生与N-甲基-D-天冬氨酸(NMDA)受体发生交叉反应且能够介导兴奋性毒性死亡的抗DNA抗体。我们现在表明,经抗原诱导表达这些抗体的小鼠,在血脑屏障发生破坏之前没有神经元损伤。在给免疫小鼠施用脂多糖(LPS)后,抗体进入大脑。它们优先与海马神经元结合,导致神经元死亡,进而引起认知功能障碍,并在磁共振波谱上改变海马代谢。在施用LPS之前给予NMDA受体拮抗剂美金刚可预防神经元损伤。因此,全身免疫反应可在没有炎症级联反应的情况下导致认知障碍,这表明免疫系统在人类病理生物学的另一个领域中发挥作用。此外,NMDA受体拮抗剂可预防抗体介导的损伤,可能构成SLE治疗的一种新方法。