PDF(Pubmed)
Abstract：
The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs.
摘要：
传统上，与皮质发育（MCD）畸形相关的癫痫综合征癫痫发作的发展归因于异常网络兴奋性引起的内在皮质改变。然而,最近对来自MCD患者的人脑样本的单细胞分辨率进行的分析表明,适应性免疫可能参与了这些疾病的发病机制.通过利用甲基偶氮甲醇（MAM）/毛果芸香碱（MP）与MCD相关的耐药性癫痫大鼠模型，我们在这里显示，癫痫持续状态的发生和随后的自发性复发性癫痫发作畸形，但不是在正常的大脑中，与具有脑炎样特征的破坏性自身免疫反应的爆发有关，涉及细胞介导和体液免疫反应的成分。MP脑的特征是血脑屏障功能障碍，显著和持续的CD8+T细胞侵袭脑实质，脑膜B细胞积累，和补体依赖性细胞毒性介导的抗神经元抗体。此外，免疫调节药物芬戈莫德对MP大鼠的治疗性治疗可促进抗癫痫和神经保护作用。总的来说，这些数据表明，MP大鼠可以作为与中枢神经系统自身免疫反应相关的癫痫性皮质畸形的转化模型。这项工作表明，先前存在的大脑发育不良倾向于继发性自身免疫反应，它是癫痫的诱发因素，并建议免疫干预作为一种治疗选择，在与MCD相关的癫痫综合征中需要进一步探索。
