P4 Impact of IgLON5 autoantibodies on cerebellar circuits and neuronal pathology in human patients and mouse models

抗IgLON5疾病是一种新型的自身免疫性脑炎，与抗细胞粘附分子IgLON5的抗体相关，以步态障碍、睡眠异常和脑干功能障碍为特征。尸检研究显示，一些患者的脑干和小脑有一种特殊的tau病变，而另一些患者仅表现为炎症浸润，并伴有IgG1和4的不同沉积。抗iglon5相关症状的突触和神经元机制在很大程度上仍然未知。因此，我们建议对9例IgLON5患者的尸检组织（6例有/ 3例没有）进行全面的神经病理学调查，以研究炎症，其对神经元的影响以及与神经退行性变的有趣联系。接下来，我们将探讨不同IgG亚类在原代培养中对神经元健康的作用。为了深入了解控制神经元功能障碍的病理机制，我们将建立基于被动IgG1或IgG4脑室内转移的小鼠疾病模型，表征抗iglon5的结合模式，从而导致行为缺陷，并通过双光子成像评估行为小鼠小脑皮层的神经元结构和功能。

Anti-IgLON5 disease is a novel form of autoimmune encephalitis, associated with antibodies against the cell-adhesion molecule IgLON5 and characterized by gait impairment, sleep abnormality and brainstem dysfunction. Autopsy studies revealed a peculiar tauopathy in the brainstem and cerebellum in some patients, while others show inflammatory infiltrates only, with variable deposits of IgG1 and 4. The synaptic and neuronal mechanisms underlying the anti-IgLON5-associated symptoms remain largely unknown. We thus propose to conduct comprehensive neuropathological investigations of autopsy tissue of nine IgLON5 patients (six with/three without tauopathy), to study inflammation, its impact on neurons and the intriguing link to neurodegeneration. We will next probe the role of different IgG subclasses on neuronal health in primary cultures. To gain insight into the pathomechanisms governing neuronal dysfunction, we will establish a mouse model of disease based on passive IgG1 or IgG4 intracerebroventricular transfer and characterize the binding pattern of anti-IgLON5, resulting behavioral deficits and assess neuronal structure and function in the cerebellar cortex of behaving mice by means of two-photon imaging.