Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK.
Neurology Section, Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy.
Brain. 2022 Dec 19;145(12):4287-4307. doi: 10.1093/brain/awac232.
Organized 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 CSF 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 subclinical immunization with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localized overexpression 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 previous myelin oligodendrocyte glycoprotein immunization, the neuronal loss was present irrespective of immunization. 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.
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，但涉及的机制尚未解决。淋巴毒素-α在淋巴器官发育和免疫系统中的细胞细胞毒性中发挥关键作用，其在幼稚和进展性多发性硬化症患者和死后脑膜组织的 CSF 中表达增加。在这里，我们表明脑膜中持续增加的淋巴毒素-α水平可导致类淋巴样结构和潜在的多发性硬化样皮质病理学。重组淋巴毒素-α立体定向注射到大鼠脑膜中可导致急性脑膜炎症和软脑膜下脱髓鞘，28 天后可缓解，脱髓鞘依赖于先前用髓鞘少突胶质细胞糖蛋白进行亚临床免疫接种。将淋巴毒素-α慢病毒载体注入皮质脑膜空间，以产生细胞因子的慢性局部过表达，可诱导广泛的类淋巴样免疫细胞聚集，持续 3 个月以上，包括富含 podoplanin+成纤维细胞网状基质细胞的 T 细胞丰富区和富含滤泡树突状细胞的 B 细胞丰富区，以及淋巴趋化因子及其受体的表达。在下面的皮质实质中发生广泛的小胶质细胞和星形胶质细胞激活、软脑膜下脱髓鞘和明显的神经元丢失。虽然软脑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接种，但神经元丢失与免疫接种无关。来自 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，单独慢性淋巴毒素-α过表达足以诱导脑膜类淋巴样结构的形成和随后的神经退行性变，类似于在进行性多发性硬化症大脑中所见。
