Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood–brain barrier opening, periventricular T₂-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220⁺ (B cell) infiltration towards the ventricles, where they differentiated into CD138⁺ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.

中文翻译：

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由针对N-甲基-d-天冬氨酸受体的B细胞反应介导的自身免疫性脑炎。

抗Ñ甲基d天冬氨酸受体（NMDAR）脑炎是神经精神疾病，其特征针对NMDAR抗体介导的自身免疫反应。最近的研究表明，抗NMDAR抗体与疾病的病理生理有关。然而，仍不清楚这种病原反应的上游免疫和炎症过程。在这里，我们针对含有N368 / G369氨基酸的NMDA受体区域免疫了小鼠，该区域先前与致病反应有关。这种范例诱发的脑病的特征是血脑屏障打开，脑室周围T ₂-MRI高信号和IgG沉积到脑实质中。免疫后两周，小鼠出现了让人联想到脑炎的临床症状：焦虑和抑郁样行为，空间记忆障碍（无运动障碍）以及对癫痫发作的敏感性增加。该反应独立于明显的T细胞募集而发生。然而，它与脑室的B220 ⁺（B细胞）浸润有关，并分化为CD138 ⁺细胞（浆细胞）。有趣的是，这些B细胞起源于外周淋巴器官（脾和颈淋巴结）。最后，使用耗尽的抗体混合物阻断B细胞反应可降低脑炎小鼠的症状严重程度。这项研究表明，B细胞反应可导致针对NMDAR的自身免疫反应，从而引发脑炎样行为障碍。它还为解剖动物模型中的致脑病机制提供了相关平台，并能够测试针对抗NMDAR脑炎的免疫系统的治疗策略。