Background Multiple 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 risk outweighing benefit.

Objective This study aims to examine the effect of age on DAs and the peripheral production of Myelin Basic Protein (MBP)-driven cytokine response in pwMS.

Methods We included the clinical data of 368 adult pwMS between 2017 and 2021 from a clinic-based registry. In a subset of 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 IL-17 and IFN-γ using Enzyme-Linked Immunosorbent Assay. We further analyzed a subset of the supernatant samples using the Luminex xMAP platform human cytokine/chemokine array. We examined associations between age and inflammatory DA [annualized relapse rate (ARR)] as well as age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regression. We determined the extent of the MBP-driven cytokine responses in driving the association between age and ARR using mediation analyses.

Results Among 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 with cultured PBMC, MBP-driven 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). Further, older pwMS (≥50 years) had significantly lower (IL-4, MCP2, MCP3, PDGF.AA, PDGF.AB.BB) and higher (Fractalkine, MDC) concentrations of several cytokines when compared to younger pwMS (<50 years). These cytokines affected the association between age and ARR in different ways, with some of them (MCP-2 and MDC) likely mediating the effect of age on ARR, while the others likely counteracting the effect of age on ARR.

Conclusion This study suggests some of the potential biological mechanisms driving aging-dependent decline in MS inflammatory DA.

The authors have declared no competing interest.

This study did not receive any funding

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The institutional review boards of the University of Pittsburgh gave ethical approval for this work (STUDY19080007).

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