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.
Keywords: IRIS; JC virus; PML; natalizumab; progressive multifocal leukoencephalopathy.
© 2015 Japanese Society of Neuropathology.