Organised meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the cerebrospinal fluid of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of lymphotoxin alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology. Stereotaxic injections of recombinant lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and subpial demyelination that resolved after 28 days, with demyelination being dependent on prior sub-clinical immunisation with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localised over-expression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial and astroglial activation, subpial demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial demyelination was partially dependent on prior myelin oligodendrocyte glycoprotein immunisation, the neuronal loss was present irrespective of immunisation. Conditioned medium from LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive multiple sclerosis brain.

中文翻译：

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脑膜中的淋巴毒素-α 表达导致淋巴组织形成和神经变性

有组织的脑膜免疫细胞浸润被认为在多发性硬化症大脑的皮质灰质病理学中发挥重要作用，但所涉及的机制尚未得到解决。淋巴毒素-α 在免疫系统的淋巴器官发育和细胞毒性中起关键作用，其表达在幼稚和进行性多发性硬化症患者的脑脊液和死后脑膜组织中增加。在这里，我们表明脑膜中淋巴毒素 alpha 水平持续升高会导致淋巴样结构和潜在的多发性硬化样皮质病理学。将重组淋巴毒素-α 立体定向注射到大鼠脑膜中导致急性脑膜炎症和软膜下脱髓鞘，28 天后消退，脱髓鞘依赖于先前用髓鞘少突胶质细胞糖蛋白进行的亚临床免疫。将淋巴毒素-α 慢病毒载体注射到皮质脑膜间隙，以产生细胞因子的慢性局部过度表达，诱导广泛的淋巴样免疫细胞聚集，维持超过 3 个月，包括含有 podoplanin + 成纤维细胞网状基质的 T 细胞丰富区细胞和富含 B 细胞的区域以及滤泡树突状细胞网络，以及淋巴趋化因子及其受体的表达。广泛的小胶质细胞和星形胶质细胞激活、软膜下脱髓鞘和显着的神经元丢失发生在下面的皮质实质中。而软膜下脱髓鞘部分依赖于先前的髓鞘少突胶质细胞糖蛋白免疫，无论免疫接种如何，神经元丢失都存在。来自经 LTα 处理的小胶质细胞的条件培养基能够在星​​形胶质细胞中诱导反应性表型。我们的结果表明，仅慢性淋巴毒素-α 过度表达就足以诱导脑膜淋巴样结构的形成和随后的神经变性，类似于在进行性多发性硬化症大脑中所见。