Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Sci Transl Med. 2019 Jul 10;11(500). doi: 10.1126/scitranslmed.aaw0044.
Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of autoantibodies to -methyl-d-aspartate (NMDA) receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, and seizures that could lead to long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here, we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immunocompetent mice with conformationally stabilized, native-like NMDA receptors induced a fulminant encephalitis, consistent with the behavioral and pathologic characteristics of human cases. Our results provide evidence for neuroinflammation and immune cell infiltration as components of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells and antibody-producing cells were required for disease induction. This active immunization model may provide insights into disease induction and a platform for testing therapeutic approaches.
中枢神经系统膜蛋白自身免疫已被越来越多地认为是神经精神疾病的一个原因。最近的一个重要发现是，在一些脑炎病例中发现了抗 -甲基-d-天冬氨酸 (NMDA) 受体的自身抗体，其特征是认知改变、记忆丧失和癫痫发作，可能导致长期发病或死亡。治疗方法和实验研究主要集中在这些自身抗体的致病作用上。被动抗体转移到小鼠中提供了有用的见解，但不能产生人类疾病的全部谱。在这里，我们描述了一种新型的抗 NMDA 受体脑炎自身免疫小鼠模型。用构象稳定的、类似天然的 NMDA 受体对免疫功能正常的小鼠进行主动免疫接种，可诱导暴发性脑炎，与人类病例的行为和病理特征一致。我们的结果为免疫反应中的神经炎症和免疫细胞浸润提供了证据。使用转基因小鼠表明，成熟的 T 细胞和产生抗体的细胞是疾病诱导所必需的。这种主动免疫模型可能为疾病诱导提供见解，并为测试治疗方法提供平台。
