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

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.

Keywords: John Cunningham virus; dimethyl fumarate; fingolimod; glia; natalizumab.

Figure 1

Immunosuppressive activities of multiple sclerosis (MS) therapies facilitate John Cunningham virus (JCV) infection and replication in the central nervous system (CNS). MS immunomodulatory therapies associated with progressive multifocal leukoencephalopathy have different mechanisms of action, but ultimately lead to an immunosuppressed state within the CNS that increases the likelihood of a productive infection of glial cells by JCV, represented as the uncontrolled JCV state. (1) In a healthy immune system (or the absence of immunomodulatory therapy), lymphocytes can enter the CNS via the blood–brain barrier, blood–meningeal barrier, or blood–cerebrospinal fluid barrier (latter two not shown), and JCV infected B-cells have been proposed as carriers of the virus into the CNS. In contrast, MS therapies block CNS entry of specific lymphocyte subsets: (2) natalizumab prevents CNS access of α4 integrin expressing lymphocytes primarily across the BBB by blocking α4β1/vascular cell adhesion molecule 1 (VCAM-1) adhesion interactions; (3) fingolimod traps within lymph nodes the lymphocytes that utilize sphingosine-1-phosphate 1 (S1P1) receptors for homing; (4) dimethyl fumarate interferes with the maturation of Th1 T-lymphocytes, tipping the balance in favor of anti-inflammatory Th2 cells. (5) Within the CNS, the net effect reduced the entry of conventional lymphocytes secreting pro-inflammatory IFN-γ and a relatively higher percentage of interleukin-10 (IL-10)-producing anti-inflammatory regulatory lymphocytes, compared to the healthy/untreated state. (6) The altered cytokine profile affects cross-talk between lymphocytes and CNS-resident astrocytes leading to transcriptional changes, such as the suppression of SRSF1, which can promote viral T-antigen expression, reactivation, and replication. (7) The JCV-infected astrocytes could then pass on the virus to oligodendrocytes and (8) fail to properly recruit the subset of lymphocytes necessary to clear the virus. (9) While most are blocked, the JCV specific T-cells that are present fail to adequately clear JCV (Image copyright: Caitlyn Fisher and Yang Mao-Draayer, reprints use with permission).

Figure 2

Convergence of peripheral immune changes, central nervous system (CNS) glial infectivity, and genetic susceptibility in the development of progressive multifocal leukoencephalopathy (PML). Whether a multiple sclerosis (MS) patient treated with immunomodulatory therapy will develop PML depends on changes in the peripheral immune system (blue) that lead to immunosuppression, particularly within the CNS (green), and in a genetic background (purple) that increases the susceptibility of glial cells to productive infection by John Cunningham virus (JCV). Risk increases as the circles get smaller, but a patient will not develop PML until they experience all three events located within the innermost circle: the loss of number/function of JCV-specific T-cells within the CNS in the context of a lytic JCV infection within oligodendrocytes by a version of JCV with a mutated non-coding regulatory region (NCCR). The failure of current assessments to accurately predict risk lies in the failure of these metrics to take into account all three facets. New analytics need to take into account JCV-specific lymphocyte function, JCV genetic variants, and the location of latent JCV within the body of a particular MS patient (Image copyright: Caitlyn Fisher and Yang Mao-Draayer, reprints with permission).