Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients

Abstract

New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

“…It has been well established that the percentage and absolute numbers of total B cells and memory B cells are elevated in NAT treated MS patients [22,23]. In line with these results, we also observed an increase in relative B cell numbers and a trend towards increased absolute total B cell numbers and memory B cell counts and percentages.…”

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…Moreover, aging and T cell immunoscenescence has been associated with MS and EAE [158]), as well as with other autoimmune diseases [159,160]). Furthermore, treatment efficacy and development of progressive multifocal leukoencephalopathy in MS patients has been linked and associated with immunoscenescence [161][162][163]. As the role of the aging immune system in infectious diseases and autoimmunity appears somewhat contradictory [160], an interesting question is how does the inflammatory environment during aging/immunoscenescence contribute to and modulate autoimmune memory?…”

CD4+CD62L+ cells: A monitoring marker of fingolimod dosage in multiple sclerosis

“…Herpes zoster infection is a common clinical problem, especially among adults aged ≥50 years and immunocompromised patients, 18 and the infection was observed in 10 of 15 FTY-PML patients aged >50 years. 19 Previously, the lack of CD62L in cryopreserved CD4 + T cells was reported to be a biomarker for a higher risk of PML onset in patients with MS treated using natalizumab; 20 however, cryopreserved lymphocytes showed low cellular viability, and the findings remain debatable, because an independent study did not validate this observation. 19 Previously, the lack of CD62L in cryopreserved CD4 + T cells was reported to be a biomarker for a higher risk of PML onset in patients with MS treated using natalizumab; 20 however, cryopreserved lymphocytes showed low cellular viability, and the findings remain debatable, because an independent study did not validate this observation.…”