Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease.
Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease.
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DOI：
10.1038/s41582-020-00427-y
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Nath A
中科院分区：
文献类型：
--
作者：
Cortese I;Reich DS;Nath A
进行性多灶性白质脑病（PML）是一种由JC病毒（JCV）引起的破坏性中枢神经系统感染，JC病毒是一种多瘤病毒，通常在普通人群中造成持续无症状感染。新的证据表明PML可以通过新的免疫治疗方法改善，这要求重新评估PML的病理生理和临床过程。PML是在细胞免疫受损的情况下由JCV再激活引起的，并且没有可用的抗病毒治疗，因此生存取决于潜在免疫抑制的逆转。抗逆转录病毒疗法大大降低了艾滋病毒相关PML的风险，但许多针对癌症、器官移植和慢性炎症性疾病的现代治疗方法会导致难以逆转的免疫抑制。这些治疗——最著名的是用于多发性硬化症的那他珠单抗——导致医源性PML的激增。随着时间的推移，jcv相关疾病的表现谱不断变化，可能会挑战当前的诊断标准。免疫治疗干预，如使用检查点抑制剂和过继T细胞转移，已经显示出希望，但在免疫重建炎症综合征的管理中需要谨慎，这是一种可能导致发病率和死亡的过度免疫反应。许多在PML中幸存下来的人都留下了神经系统后遗症，有些人在中枢神经系统中持续存在低水平的病毒复制。随着PML存活人数的增加，这种病毒清除的缺乏可能会给一些潜在疾病的后续治疗带来挑战。在这篇综述中，Cortese等人概述了JC病毒引起的进行性多灶性白质脑病和其他疾病的病理生物学和演变表现，并讨论了可以提高生存率的新兴免疫治疗方法。进行性多灶性脑白质病（PML）是由JC病毒（JCV）引起的一种罕见的、使人衰弱的、经常致命的中枢神经系统疾病。JCV可在免疫能力强的宿主中建立无症状、终身持续或潜伏感染，但细胞免疫功能受损可导致JCV和PML的再激活。PML最常见于HIV感染或淋巴增生性疾病患者以及接受纳他珠单抗治疗多发性硬化症的患者。PML的临床表型各不相同，主要由宿主免疫反应决定；随着时间的推移，与PML相关的基础疾病治疗的改变改变了表型。已经描述了JCV感染的其他临床表现，包括颗粒细胞神经病变。PML的生存取决于潜在免疫抑制的逆转；新兴的免疫治疗策略包括使用检查点抑制剂和过继性T细胞转移。
Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent, asymptomatic infection in the general population. Emerging evidence that PML can be ameliorated with novel immunotherapeutic approaches calls for reassessment of PML pathophysiology and clinical course. PML results from JCV reactivation in the setting of impaired cellular immunity, and no antiviral therapies are available, so survival depends on reversal of the underlying immunosuppression. Antiretroviral therapies greatly reduce the risk of HIV-related PML, but many modern treatments for cancers, organ transplantation and chronic inflammatory disease cause immunosuppression that can be difficult to reverse. These treatments — most notably natalizumab for multiple sclerosis — have led to a surge of iatrogenic PML. The spectrum of presentations of JCV-related disease has evolved over time and may challenge current diagnostic criteria. Immunotherapeutic interventions, such as use of checkpoint inhibitors and adoptive T cell transfer, have shown promise but caution is needed in the management of immune reconstitution inflammatory syndrome, an exuberant immune response that can contribute to morbidity and death. Many people who survive PML are left with neurological sequelae and some with persistent, low-level viral replication in the CNS. As the number of people who survive PML increases, this lack of viral clearance could create challenges in the subsequent management of some underlying diseases. In this Review, Cortese et al. provide an overview of the pathobiology and evolving presentations of progressive multifocal leukoencephalopathy and other diseases caused by JC virus, and discuss emerging immunotherapeutic approaches that could increase survival. Progressive multifocal leukoencephalopathy (PML) is a rare, debilitating and often fatal disease of the CNS caused by JC virus (JCV). JCV establishes asymptomatic, lifelong persistent or latent infection in immune competent hosts, but impairment of cellular immunity can lead to reactivation of JCV and PML. PML most commonly occurs in patients with HIV infection or lymphoproliferative disease and in patients who are receiving natalizumab for treatment of multiple sclerosis. The clinical phenotype of PML varies and is shaped primarily by the host immune response; changes in the treatment of underlying diseases associated with PML have changed phenotypes over time. Other clinical manifestations of JCV infection have been described, including granule cell neuronopathy. Survival of PML depends on reversal of the underlying immunosuppression; emerging immunotherapeutic strategies include use of checkpoint inhibitors and adoptive T cell transfer.
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