PDF(Pubmed)
Abstract：
Background: Anti-IgLON5 disease is a rare autoimmune disease of the central nervous system. It typically manifests as a chronic condition, characterized by cognitive impairments, movement disorders, and sleep disorders. The mechanisms underlying movement disorders in this disease remain poorly understood due to a lack of research. Furthermore, this disease exhibits both neuroimmune and neurodegenerative characteristics. The objective of this study is to explore the underlying mechanisms of movement disorders caused by anti-IgLON5 antibodies for the first time. Methods: Antibodies were purified from the serum of a confirmed patient of anti-IgLON5 disease. The passive transfer animal models were employed, where antibodies were continuously injected into the substantia nigra pars compacta (SNc) of the mouse midbrain using stereotactic injection to explore the mechanism of movement disorder. The effects of anti-IgLON5 antibodies on dopaminergic neurons in the SNc and neurodegeneration were examined through immunohistochemistry. Changes in neurotransmitter levels in the basal ganglia were assessed using high-performance liquid chromatography. Additionally, RNA-seq was employed to identify the differentially expressed genes associated with the short-term and long-term effects of anti-IgLON5 antibody on the SNc. Results: Mice injected with anti-IgLON5 antibodies in the SNc exhibited persistent movement impairments for up to 3 months. One week after antibody injection, the number of TH neurons significantly decreased compared to the control group, accompanied by reduced projection fibers in the basal ganglia and decreased dopamine levels. After 3 months of antibody injection, an increase in phosphorylated Tau was observed in the SNc of the midbrain. Additionally, long-term sustained activation of microglia was detected in the SNc. The differentially expressed genes of long-term effects of IgLON5 antibodies were different from their short-term effects on the SNc. Conclusion: Purified serum IgG from a patient with anti-IgLON5 antibodies can cause long-term movement disorder in mice. The movement disorders appear to be linked to the impaired dopaminergic pathway, and the increased p-Tau showed neurodegenerative changes induced by the anti-IgLON5 antibody.
摘要：
配景：抗IgLON5病是一种罕见的中枢神经体系本身免疫性疾病。它通常表现为慢性病，以认知障碍为特征，运动障碍,和睡眠障碍。由于缺乏研究，这种疾病中运动障碍的潜在机制仍然知之甚少。此外，这种疾病表现出神经免疫和神经退行性特征。本研究的目的是首次探讨抗IgLON5抗体引起运动障碍的潜在机制。方法：从确诊的抗IgLON5病患者的血清中纯化抗体。采用被动转移动物模型，其中使用立体定向注射将抗体连续注射到小鼠中脑的黑质致密部（SNc）中，以探索运动障碍的机制。通过免疫组织化学检查了抗IgLON5抗体对SNc和神经变性中多巴胺能神经元的影响。使用高效液相色谱法评估基底神经节中神经递质水平的变化。此外,RNA-seq用于鉴定与抗IgLON5抗体对SNc的短期和长期影响相关的差异表达基因。结果：在SNc中注射抗IgLON5抗体的小鼠表现出持续的运动障碍长达3个月。抗体注射后一周，与对照组相比，TH神经元数量显著减少，伴有基底神经节投射纤维减少和多巴胺水平降低。注射抗体3个月后，在中脑的SNc中观察到磷酸化Tau的增加。此外,在SNc中检测到小胶质细胞的长期持续激活。IgLON5抗体的长期效应的差异表达基因与它们对SNc的短期效应不同。结论:含有抗IgLON5抗体的患者纯化血清IgG可引起小鼠长期运动障碍。运动障碍似乎与受损的多巴胺能途径有关，增加的p-Tau显示出抗IgLON5抗体诱导的神经退行性变化。
