Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.

中文翻译：

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脂质特异性IgM在CNS中诱导抗病毒反应：对多发性硬化中进行性多灶性白质脑病的影响。

进行性多灶性白质脑病（PML）是由JC多瘤病毒（JCV）引起的潜在致命性脑炎。PML主要影响免疫系统受损的人，例如接受那他珠单抗治疗的多发性硬化症（MS）患者。然而，与没有该抗体库的患者相比，MS患者鞘内合成脂质反应性IgM与那他珠单抗相关的PML发生率显着降低。在这里，我们证明了脂质反应性人类和鼠类IgM的子集可诱导功能性抗病毒反应，该反应可抑制多细胞中枢神经系统培养物中脑性Alpha和Orthobunyaviruses的复制。这些脂质特异性IgM触发小胶质细胞以cGAS-STING依赖性方式产生IFN-β，在胶质细胞和神经元中诱导IFN-α/β受体1依赖性抗病毒反应。这些数据将脂质反应性IgM鉴定为神经系统抗病毒活性的介质，并提供了合理的解释，说明鞘内脂质反应性IgM的合成与MS中医源性PML发生率降低相关。