Shishido-Hara Yukiko
Department of Pathology, School of Medicine, Kyorin University, Tokyo, Japan.
Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Neuropathology. 2015 Oct;35(5):487-96. doi: 10.1111/neup.12203. Epub 2015 May 6.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC (JC virus). The pathology of affected brain tissues demonstrates oligodendroglia-like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot-shaped inclusions). The dot-shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early-stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti-viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus-host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a focus on the intranuclear target of JC virus infection and host inflammatory reactions.
进行性多灶性白质脑病（PML）是一种由无症状持续性病原体人多瘤病毒JC（JC病毒）重新激活引起的致命性脱髓鞘疾病。受影响脑组织的病理学表现为少突胶质样细胞，其细胞核增大并含有病毒包涵体，这是该疾病的诊断标志。如今，这种疾病的病理特征正在扩展，部分原因是病毒毒力与宿主免疫力之间的平衡不稳定。基于苏木精-伊红染色（完全包涵体），核内病毒包涵体最初被认为是包含整个增大细胞核的嗜双色性物质。然而，最近的免疫组织化学分析检测到点状核内病毒包涵体（点状包涵体）的存在。点状包涵体反映了在称为早幼粒细胞白血病核体的间断性核内亚域聚集的子代病毒粒子，指示早期病毒感染或病毒增殖受抑制。其次，JC病毒通常在免疫功能受损的患者中重新激活，因此炎症反应较弱。然而，免疫抑制的原因各不相同，如频繁使用包括那他珠单抗在内的免疫抑制药物。因此，宿主免疫程度是可变的；一些患者表现出明显的抗病毒炎症反应和良好预后，表明对病毒感染仍有较强抵抗力。免疫系统的恢复也可能导致矛盾的临床恶化，即免疫重建炎症综合征，其机制尚未阐明。病毒-宿主相互作用的复杂性增加，PML的病理学也在分化。在本综述中，将描述PML的病理学，重点是JC病毒感染的核内靶点和宿主炎症反应。
