Pathogenesis of Progressive Multifocal Leukoencephalopathy—Revisited

Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.

Neoplasm Related Encephalopathies

“…However, to some degree there is a consensus about the major steps that need to be fulfilled for the development of PML (table 7). These steps include: primary infection with JCV, period of latent infection, reactivation of JCV and eventually invasion into the brain (Brew et al, 2010;Major, 2010;White and Khalili, 2011).…”

“…Primary infection occurs mainly in the childhood but continues into middle age. JCV is a hemagglutinating virus and hemagglutination inhibition assays were able to detect JCV antibodies in 50-90% of adults (Taguchi et al, 1982 andWalker andPadgett, 1983 as cited in White and Khalili, 2011). The route of transmission is believed to be inhalation of the virus with infection of the tonsils or ingestion of contaminated water or food and uptake of the virus by the gastro-intestinal tract.…”

“…Based upon detection of JCV in urine and the presence of JCV DNA in tissue of PML and non-PML patients, at least 3 organs are believed to harbor latent infection: the kidney, the bone marrow and lymphoid tissues like the tonsils, spleen, B-lymphocytes and CD 34+ hematopoetic cells (Major, 2010;White and Khalili, 2011).…”

“…Although prototype JCV-DNA has been found in normal non-PML brain tissue (White and Khalili, 2011), some investigators question the possibility of the brain as a functional latency site given the rarity of PML and the unlikeliness of establishing a long-term latency without inflammatory consequences during viral clearance (Major, 2010).…”

“…The most popular theory is reactivation of JCV in peripheral blood mononuclear cells causing hematogenous dissemination of the virus across the body with B-lymphocytes having the ability to cross the blood-brain barrier (Berger et al, 2009;Brew et al, 2010;White and Khalili, 2011). …”