Aging-dependent Change in Th17 and Cytokine Response in Multiple Sclerosis

Abstract

AbstractBackgroundMultiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activities (DAs) as people with MS (pwMS) age justified randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits.ObjectiveThis study aims to examine the effect of age on DAs and the peripheral production of Myelin Basic Protein (MBP)-driven cytokine response in pwMS.MethodsWe included the clinical data of 368 adult pwMS between 2017 and 2021 who enrolled in a clinic-based prospective cohort. From 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50μg/ml of MBP for 24 hours. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine responses drive the association between age and ARR.ResultsAmong the 386 pwMS (mean age 53.1±12.6 years, 79.9% women, 92.1% non-Hispanic White), ARR declined with age (β=-0.003, p<0.001). Among the 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p=0.04) but not men (β=-0.1, p=0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.7% in women, 15.3% in men). In exploratory analysis, older pwMS (≥50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (<50 years). Some cytokines (MCP-2, MDC) mediate while others negate the effect of age on ARR.ConclusionThis study suggests some of the potential biological mechanisms driving aging-dependent decline in MS inflammatory DA that warrant further investigation.