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Progressive Multifocal Leukoencephalopathy and Apoptosis of Infected Oligodendrocytes in the Central Nervous System of Patients With and Without AIDS
Sarah M. Richardson-Burns, MS;
B. K. Kleinschmidt-DeMasters, MD;
Roberta L. DeBiasi, MD;
Kenneth L. Tyler, MD
Arch Neurol. 2002;59:1930-1936.
Context Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV) that occurs in immunocompromised patients. Demyelination of the CNS is a consequence of virus-induced killing of oligodendrocytes, although the exact mechanism of cell death is unknown.
Objective To examine archival autopsy and surgical pathologic specimens from 8 patients with PML, including 6 patients with human immunodeficiency virus (HIV)-associated PML and 2 patients with non-HIV–associated PML, for evidence of apoptosis.
Design Apoptotic cells were identified by TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end in situ labeling) or immunohistochemical detection of activated caspase 3. The JCV-infected cells were identified by in situ hybridization for viral transcripts or immunohistochemical analysis for JCV T antigen.
Results Apoptosis of JCV-infected oligodendrocyte apoptosis was a prominent feature in all cases of both HIV- and non–HIV-associated PML. There were no differences between number or distribution of apoptotic cells identified by TUNEL or immunohistochemical analysis for activated caspase 3. Bizarre astrocytes were occasionally positive for JCV but were not apoptotic. Neurons, astrocytes, macrophages, and oligodendrocytes remote from lesions were neither apoptotic nor JCV infected.
Conclusions Our study demonstrates that apoptosis occurs in oligodendrocytes associated with demyelinated lesions of patients with both HIV-associated and non–HIV-associated PML. There were no differences in degree, location, or type of infected or apoptotic cells between patients with HIV-associated and non–HIV-associated PML. The extent of apoptosis did not correlate with the presence or intensity of host inflammatory response. Accumulation of viral particles in nuclei of infected cells made it difficult to identify morphologic changes in the nucleus typically associated with apoptosis.
From the Neuroscience Program (Ms Richardson-Burns and Dr Tyler) and Departments of Neurology (Drs Kleinschmidt-DeMasters, DeBiasi, and Tyler), Pathology (Dr Kleinschmidt-DeMasters), Pediatrics (Dr DeBiasi), Medicine (Dr Tyler), Immunology (Dr Tyler), and Microbiology (Dr Tyler), University of Colorado Health Sciences Center and Denver Veterans Affairs Medical Center (Drs DeBiasi and Tyler), Denver.
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