Wilke Justus, Ntolkeras Antonios, Gastaldi Vinicius Daguano, Borowski Kathrin, Teegen Bianca, Stöcker Winfried, Lühder Fred, Nave Klaus-Armin, Ehrenreich Hannelore
Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, Germany.
Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
Sci Rep. 2025 Jun 27;15(1):20337. doi: 10.1038/s41598-025-08035-w.
Patients with virus encephalitis, such as herpes simplex encephalitis and Japanese encephalitis frequently relapse with autoimmune encephalitides associated with neural autoantibodies. It has been hypothesized that the infection-induced damage to the central nervous system results in shedding of neural autoantigens, their presentation to the peripheral immune system, and initiation of a secondary autoimmune encephalitis that targets these autoantigens. To test this hypothesis, we utilized a transgenic mouse model of virus-like but sterile encephalitis. After induction of acute neuronal death in the hippocampus, we monitored the mice for encephalitis-like symptoms for up to 10 months, evaluated the degree of neuroinflammation at several time points and screened their plasma for autoantibodies against 49 different autoimmune disease-associated brain autoantibodies. Throughout the study period, we did not detect any symptoms of severe autoimmune encephalitis, like hyperactivity, circling, seizures, lethargy. Evaluation of microglia numbers and morphology revealed pronounced microgliosis 1-week after initial encephalitis induction, which decreased over time. Scattered lymphocyte infiltration was present at all times in hippocampi of encephalitis mice, and did not increase over time. Perivascular cuffs were not detected. Infiltrating lymphocytes mainly consisted of CD8+ T cells. B cell infiltration was rare and did not differ from healthy control mice. High-parameter immunophenotyping of peripheral blood leukocytes did not reveal any changes associated with an autoimmune response. Testing all plasma samples (n = 30/group) at a dilution of 1:100 for autoantibodies against 49 neural autoantigens gave only two positive results, namely one healthy control with anti-CASPR2 autoantibodies (IgG) and one post-encephalitis mouse with anti-homer-3 autoantibodies (IgM). Overall, these findings suggest that acute neuronal cell death and neuroinflammation per se are not sufficient to trigger downstream autoimmune encephalitis relapses in mice.
病毒脑炎患者，如单纯疱疹病毒性脑炎和日本脑炎患者，常与神经自身抗体相关的自身免疫性脑炎反复复发。据推测，感染引起的中枢神经系统损伤导致神经自身抗原脱落，这些抗原呈递给外周免疫系统，并引发针对这些自身抗原的继发性自身免疫性脑炎。为了验证这一假设，我们使用了一种类似病毒但无菌性脑炎的转基因小鼠模型。在诱导海马体急性神经元死亡后，我们对小鼠进行了长达10个月的脑炎样症状监测，在几个时间点评估神经炎症程度，并在其血浆中筛查针对49种不同自身免疫性疾病相关脑自身抗体的自身抗体。在整个研究期间，我们未检测到任何严重自身免疫性脑炎的症状，如多动、转圈、癫痫发作、嗜睡。对小胶质细胞数量和形态的评估显示，在最初诱导脑炎后1周出现明显的小胶质细胞增生，随时间推移而减少。脑炎小鼠海马体中始终存在散在的淋巴细胞浸润，且不随时间增加。未检测到血管周围套袖现象。浸润的淋巴细胞主要由CD8 + T细胞组成。B细胞浸润很少见，与健康对照小鼠无差异。外周血白细胞的高参数免疫表型分析未发现与自身免疫反应相关的任何变化。以1:100的稀释度检测所有血浆样本（每组n = 30）中针对49种神经自身抗原的自身抗体，仅得到两个阳性结果，即1例具有抗CASPR2自身抗体（IgG）的健康对照和1例具有抗homer - 3自身抗体（IgM）的脑炎后小鼠。总体而言，这些发现表明急性神经元细胞死亡和神经炎症本身不足以触发小鼠下游自身免疫性脑炎复发。
