Progressive multi-focal leucoencephalopathy – driven from rarity to clinical mainstream by iatrogenic immunodeficiency

Abstract

SummaryAdvances in immune-mediated targeted therapies have proved to be a doubleedged sword for patients by highlighting the risk of iatrogenic infective complications. This has been exemplified by progressive multi-focal leucoencephalopathy (PML), a hitherto rare devastating viral infection of the brain caused by the neurotrophic JC polyoma virus. While PML achieved prominence during the first two decades of the HIV epidemic, effective anti-retroviral treatment and restitution of T cell function has led to PML being less prominent in this population. HIV infection as a predisposing factor has now been supplanted by T cell immunodeficiency induced by a range of immune-mediated therapies as a major cause of PML. This review focuses on PML in the context of therapeutic immunosuppression and encompasses therapeutic monoclonal antibodies, novel immunomodulatory agents such as Fingolimod and dimethyl fumarate, as well as emerging data on PML in primary immune deficiency.

Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions

“…In general, these therapies are immunomodulatory, limit lymphocyte proliferation, inhibit lymphocyte trafficking, and/or protect against oxidative damage ( English and Aloi, 2015 ; Dargahi et al, 2017 ). Despite their disease efficacy, some MS therapies that deplete T-cells or that inhibit T-cell trafficking are associated with progressive multifocal leukoencephalopathy (PML), which is a rare condition caused by reactivation of the JC virus in the CNS ( Misbah, 2017 ). The association of PML with T-cell deficiency underscores a functional role for T-cells in protecting the CNS from latent viral infections and will be discussed in detail below.…”

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…JC polyomavirus (JCPyV), the causative agent of PML, is common in the general population with a reported prevalence of 30-70% and a continuous rise with age [75,76]. Drug-related PML has been described with CD4+ and CD8+ T cell deficiencies [77,78].…”

Role of LFA-1 and ICAM-1 in Cancer

“…This is the case of efalizumab, a humanized monoclonal antibody directed against CD11a, which blocks the interaction between LFA-1 and ICAM-1 [ 76 ]. Initially used in the treatment of psoriasis, it had to be withdrawn in 2009 after a high incidence of progressive multifocal leukoencephalopathy, due to reactivation of a latent infection by the neurotrophic JC polyoma virus [ 77 ]. These results underline the need to better understand the diverse functions of LFA-1.…”