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Progressive multifocal leukoencephalopathy: a review of the pathology and pathogenesis
1Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
Progressive multifocal leukoencephalopathy is an important viral opportunistic infection of oligodendrocytes leading to direct demyelination. Virus is likely disseminated to the brain via the blood. However, the timing of that dissemination with relationship to clinical disease is unknown. Important clues about viral pathogenesis have been learned by applying molecular in situ techniques to diseased brain. The oligodendrocyte is the primary target for JC virus infection, and its death is the primary reason for demyelination. Bizarre astrocytes show limited viral DNA replication but are abortively infected. Although lymphoid organs can be infected by JC virus, there is no definitive evidence that lymphoid cells carry virus into the brain at the time of immunosuppression. JC virus may be reactivated from a latent state in both the brain and in non-central nervous system (CNS) organs at the time of immunosuppression, leading to clinical disease. Future sensitive in situ studies will likely resolve controversies about pathogenesis.
Insights
JC virus causes progressive multifocal leukoencephalopathy (PML) by infecting oligodendrocytes. Reactivation from a latent state in the brain or other organs likely causes PML during immunosuppression.
Area of Science:
- Neurovirology
- Immunology
- Pathology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC virus opportunistic infection.
- The precise timing of JC virus dissemination to the brain and its role in PML pathogenesis remain unclear.
- Oligodendrocytes are the primary cellular targets, leading to demyelination, while astrocytes exhibit abortive infection.
Purpose of the Study:
- To elucidate the pathogenesis of JC virus-induced progressive multifocal leukoencephalopathy.
- To investigate the dissemination routes and reactivation potential of JC virus in the context of immunosuppression.
- To clarify the roles of different cell types and organs in JC virus infection related to PML.
Main Methods:
- Application of molecular in situ hybridization techniques to analyze diseased brain tissue.
- Investigation of JC virus DNA replication in oligodendrocytes and astrocytes.
- Examination of JC virus presence in lymphoid organs and potential for cell-mediated transport.
Main Results:
- Oligodendrocyte infection and death are the primary drivers of demyelination in PML.
- JC virus DNA replication is limited in bizarre astrocytes, indicating abortive infection.
- While lymphoid organs can harbor JC virus, definitive evidence for lymphoid cell transport to the brain during immunosuppression is lacking.
Conclusions:
- JC virus reactivation from a latent state in the central nervous system (CNS) or non-CNS organs is a likely cause of PML during immunosuppression.
- The exact mechanism of viral dissemination to the brain requires further investigation.
- Future sensitive in situ studies are crucial for resolving ongoing controversies regarding PML pathogenesis.