Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, Germany.
Department of Epileptology, University Hospital Bonn, Bonn, Germany.
Ann Neurol. 2021 Apr;89(4):666-685. doi: 10.1002/ana.26000. Epub 2021 Jan 15.
Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved.
Here, we scrutinized pathogenic consequences emerging from CD8 T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1 mice (termed "OVA-CD8 LE model").
Viral-mediated antigen transfer caused dense CD8 T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8 T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8 LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8 T cells specifically targeted OVA-expressing, SIINFEKL-H-2K -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8 T cells escorted by NK cells.
These data indicate that a CD8 T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8 T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685.
边缘性脑炎（LE）包括受影响脑结构中炎症变化的谱，包括自身抗体和淋巴细胞的存在。然而，单独的不同淋巴细胞亚群引起LE 的关键临床病理后果的潜力，潜在地诱导具有慢性自发性发作和海马硬化（HS）的颞叶癫痫（TLE）尚未解决。
在这里，我们通过重组腺相关病毒介导的模型自身抗原卵清蛋白（OVA）在 OT-I/RAG1 小鼠的 CA1 神经元中的表达来仔细研究针对海马神经元的 CD8 T 细胞产生的致病后果（称为“OVA-CD8 LE 模型”）。
病毒介导的抗原转移导致 CD8 T 细胞浸润致密，局限于海马形成，从病毒转导后第 5 天开始。流式细胞术表明，在海马侵袭之前，脑引流淋巴结中存在 CD8 T 细胞的启动。在急性模型阶段，炎症过程伴随着频繁的发作活动和海马记忆技能的损害。OVA-CD8 LE 模型第 7 天的磁共振成像扫描显示海马水肿和血脑屏障破坏，直至第 40 天转化为萎缩。CD8 T 细胞特异性靶向表达 OVA、SIINFEKL-H-2K 阳性的 CA1 神经元，并导致节段性凋亡神经退行性变、星形胶质细胞增生和小胶质细胞激活。在慢性模型阶段，小鼠表现出自发性复发性发作和持续的记忆缺陷，并且硬化的海马被 CD8 T 细胞伴随着 NK 细胞所占据。
这些数据表明，特定海马神经元的 CD8 T 细胞攻击足以诱导从 LE 转化为 TLE-HS 的 LE。有趣的是，CD8 T 细胞的作用超过了神经毒性作用，并指出它们在 LE 后 TLE 中的主要致病作用。ANN NEUROL 2021；89:666-685。
