Aging-dependent change in Th17 and cytokine response in multiple sclerosis
Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS giv...
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BMC
2025-06-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03474-8 |
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| author | Wen Zhu Shankar Revu Chenyi Chen Megan Dahl Archana Ramkumar Conor Kelly Mandy J. McGeachy Zongqi Xia |
| author_facet | Wen Zhu Shankar Revu Chenyi Chen Megan Dahl Archana Ramkumar Conor Kelly Mandy J. McGeachy Zongqi Xia |
| author_sort | Wen Zhu |
| collection | DOAJ |
| description | Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA. Methods We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50 µg/ml of MBP (or heat-killed Candida) for 24 h. 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 response drives the association between age and ARR. Results Among 669 pwMS (mean age 51.7 ± 12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p < 0.001). Among the subgroup of 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 (24.6% in women, 15.3% in men). In exploratory analyses, 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), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR. Conclusion Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation. |
| format | Article |
| id | doaj-art-3e1b5f42600c47b18a09faa20e2949f2 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-3e1b5f42600c47b18a09faa20e2949f22025-08-20T02:30:42ZengBMCJournal of Neuroinflammation1742-20942025-06-0122111410.1186/s12974-025-03474-8Aging-dependent change in Th17 and cytokine response in multiple sclerosisWen Zhu0Shankar Revu1Chenyi Chen2Megan Dahl3Archana Ramkumar4Conor Kelly5Mandy J. McGeachy6Zongqi Xia7Department of Neurology, University of PittsburghDepartment of Medicine, University of PittsburghDepartment of Neurology, University of PittsburghDepartment of Neurology, University of PittsburghDepartment of Neurology, University of PittsburghDepartment of Neurology, University of PittsburghDepartment of Medicine, University of PittsburghDepartment of Neurology, University of PittsburghAbstract Background Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA. Methods We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50 µg/ml of MBP (or heat-killed Candida) for 24 h. 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 response drives the association between age and ARR. Results Among 669 pwMS (mean age 51.7 ± 12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p < 0.001). Among the subgroup of 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 (24.6% in women, 15.3% in men). In exploratory analyses, 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), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR. Conclusion Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.https://doi.org/10.1186/s12974-025-03474-8Multiple sclerosisMyelin basic proteinTh17AgingRelapseInflammatory disease activity |
| spellingShingle | Wen Zhu Shankar Revu Chenyi Chen Megan Dahl Archana Ramkumar Conor Kelly Mandy J. McGeachy Zongqi Xia Aging-dependent change in Th17 and cytokine response in multiple sclerosis Journal of Neuroinflammation Multiple sclerosis Myelin basic protein Th17 Aging Relapse Inflammatory disease activity |
| title | Aging-dependent change in Th17 and cytokine response in multiple sclerosis |
| title_full | Aging-dependent change in Th17 and cytokine response in multiple sclerosis |
| title_fullStr | Aging-dependent change in Th17 and cytokine response in multiple sclerosis |
| title_full_unstemmed | Aging-dependent change in Th17 and cytokine response in multiple sclerosis |
| title_short | Aging-dependent change in Th17 and cytokine response in multiple sclerosis |
| title_sort | aging dependent change in th17 and cytokine response in multiple sclerosis |
| topic | Multiple sclerosis Myelin basic protein Th17 Aging Relapse Inflammatory disease activity |
| url | https://doi.org/10.1186/s12974-025-03474-8 |
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