{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:58:26Z","timestamp":1768568306127,"version":"3.49.0"},"posted":{"date-parts":[[2024,3,18]]},"group-title":"Neurology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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\u03bcg\/ml of MBP (or heat-killed Candida) for 24 hours. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-\u03b3) 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 669 pwMS (mean age 51.7\u00b112.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (\u03b2=-0.003, p&lt;0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (\u03b2=-0.27, p=0.04) but not men (\u03b2=-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 analyses, older pwMS (\u226550 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 (&lt;50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.03.17.24304425","type":"posted-content","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:10:14Z","timestamp":1710807014000},"source":"Crossref","is-referenced-by-count":0,"title":["Aging-dependent Change in Th17 and Cytokine Response in Multiple Sclerosis"],"prefix":"10.64898","author":[{"given":"Wen","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shankar","family":"Revu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenyi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Dahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Archana","family":"Ramkumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mandy J","family":"McGeachy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1500-2589","authenticated-orcid":false,"given":"Zongqi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025010222550684000_2024.03.17.24304425v3.1","doi-asserted-by":"crossref","first-page":"1207617","DOI":"10.3389\/fneur.2023.1207617","article-title":"Aging in multiple sclerosis: from childhood to old age, etiopathogenesis, and unmet needs: a narrative review","volume":"14","year":"2023","journal-title":"Front Neurol"},{"key":"2025010222550684000_2024.03.17.24304425v3.2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s11910-020-01046-2","article-title":"Impact of Age on Multiple Sclerosis Disease Activity and Progression","volume":"20","year":"2020","journal-title":"Curr Neurol Neurosci"},{"key":"2025010222550684000_2024.03.17.24304425v3.3","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14191"},{"key":"2025010222550684000_2024.03.17.24304425v3.4","first-page":"1754","article-title":"Age is a critical determinant in recovery from multiple sclerosis relapses","volume":"25","year":"2018","journal-title":"Mult Scler J"},{"key":"2025010222550684000_2024.03.17.24304425v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(23)00154-0"},{"key":"2025010222550684000_2024.03.17.24304425v3.6","doi-asserted-by":"crossref","unstructured":"Zhu W , Xia Z . 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