Understanding Progressive Multifocal Leukoencephalopathy Risk in Multiple Sclerosis Patients Treated with Immunomodulatory Therapies: A Bird's Eye View.

Elizabeth A Mills,Yang Mao-Draayer

doi:10.3389/fimmu.2018.00138

Abstract

The increased use of newer potent immunomodulatory therapies for multiple sclerosis (MS), including natalizumab, fingolimod, and dimethyl fumarate, has expanded the patient population at risk for developing progressive multifocal leukoencephalopathy (PML). These MS therapies shift the profile of lymphocytes within the central nervous system (CNS) leading to increased anti-inflammatory subsets and decreased immunosurveillance. Similar to MS, PML is a demyelinating disease of the CNS, but it is caused by the JC virus. The manifestation of PML requires the presence of an active, genetically rearranged form of the JC virus within CNS glial cells, coupled with the loss of appropriate JC virus-specific immune responses. The reliability of metrics used to predict risk for PML could be improved if all three components, i.e., viral genetic strain, localization, and host immune function, were taken into account. Advances in our understanding of the critical lymphocyte subpopulation changes induced by these MS therapies and ability to detect viral mutation and reactivation will facilitate efforts to develop these metrics.

Highlights

Progressive multifocal leukoencephalopathy (PML) is a rare polyomavirus-associated disease involving progressive damage to brain white matter that often results in permanent disability or death
Similar to the other PML-associated multiple sclerosis (MS) therapies, the ability of dimethyl fumarate (DMF) to shift the balance between IFN-γ- and IL-10-producing cells likely inhibits the effective clearance of John Cunningham virus (JCV) from the central nervous system (CNS)
The DRB1*13-DQA1*01:03-DQB1*06:03 haplotype was positively associated with JCV serostatus [205]. These findings suggest that Human leukocyte antigen (HLA) typing may be useful in the stratification of patients at risk for PML

Summary

Introduction

Progressive multifocal leukoencephalopathy (PML) is a rare polyomavirus-associated disease involving progressive damage to brain white matter that often results in permanent disability or death. Relative to the total population of CD8+ T-cells, elevated levels of PD-1 have been found on the JCV-specific CD8+ T-cells of PML patients and are associated with the lack of functional response to JCV peptides [38]. Since natalizumab decreases surface expression of CD49d, longitudinal studies have indicated that lymphocyte subsets most dependent on CD49d for localization or trafficking are most affected, resulting in increased levels of conventional memory B-cells [51, 69, 70] and activated pro-inflammatory T-cells [68, 70,71,72,73] in the peripheral blood.

Results

Conclusion