{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:10:53Z","timestamp":1788909053286,"version":"build-2803163510"},"reference-count":72,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Biological Research For Nursing"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by both immune-mediated inflammation and progressive neurodegeneration. While both processes occur in all individuals with MS, females more often present with heightened inflammatory activity, whereas males tend toward accelerated neurodegeneration and disability progression. This review synthesizes current evidence on biological, hormonal, genetic, epigenetic, and environmental mechanisms underlying sex-based differences in relapsing-remitting MS (RRMS), the most common MS subtype. We integrate findings from human studies, animal models, and molecular research to examine the contribution of genetics and epigenetic regulation including sex chromosomes, single nucleotide polymorphisms (SNPs), and microRNAs (miRNAs) to MS pathophysiology. We discuss the influence of sex hormones, including estrogen, progesterone, and testosterone, and environmental risk factors such as Epstein-Barr virus infection and vitamin D3 deficiency. Evidence suggests that X-linked immune-related genes, hormone - immune interactions, and sex-specific epigenetic regulation shape differential immune responses and neuronal vulnerability in males and females with MS. miRNAs emerge as critical molecular bridges linking genetic susceptibility, hormonal milieu, and environmental exposures to downstream inflammatory and neurodegenerative pathways. Understanding the mechanisms driving sex differences in MS may enable the development of targeted interventions addressing both neuroinflammation and neurodegeneration. Integrated miRNA - mRNA analyses, explicitly powered to assess sex as a biological variable, hold promise for identifying novel biomarkers and therapeutic targets. Such approaches could inform more personalized treatment strategies and improve long-term outcomes for all people with MS.<\/jats:p>","DOI":"10.1177\/10998004251387318","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T22:34:33Z","timestamp":1760481273000},"page":"283-295","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis"],"prefix":"10.1177","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-8341","authenticated-orcid":false,"given":"Stephanie","family":"Buxhoeveden","sequence":"first","affiliation":[{"name":"Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-3193","authenticated-orcid":false,"given":"Theresa","family":"Swift-Scanlan","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5675-945X","authenticated-orcid":false,"given":"Myla D.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-5898","authenticated-orcid":false,"given":"Ryan","family":"Canissario","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-5299","authenticated-orcid":false,"given":"Unsong","family":"Oh","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17102-w"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029819"},{"issue":"1","key":"e_1_3_4_4_1","first-page":"333","article-title":"Immune cell contributors to the female sex bias in multiple sclerosis and experimental autoimmune encephalomyelitis","volume":"62","author":"Alvarez-Sanchez N.","year":"2023","unstructured":"Alvarez-Sanchez N., Dunn S. (2023). Immune cell contributors to the female sex bias in multiple sclerosis and experimental autoimmune encephalomyelitis. Current Topics in Behavioral Neurosciences, 62(1), 333\u2013373. https:\/\/doi.org\/10.1007\/7854_2022_324","journal-title":"Current Topics in Behavioral Neurosciences"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000494262"},{"issue":"3","key":"e_1_3_4_6_1","first-page":"160","article-title":"Epstein\u2013Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications","volume":"19","author":"Bjornevik K.","year":"2023","unstructured":"Bjornevik K., M\u00fcnz C., Cohen J. I., Ascherio A. (2023). Epstein\u2013Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications. Nature Reviews Neurology, 19(3), 160\u2013171. https:\/\/doi.org\/10.1038\/s41582-023-00775-5","journal-title":"Nature Reviews Neurology"},{"issue":"1","key":"e_1_3_4_7_1","article-title":"X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility","volume":"66","author":"Borziak K.","year":"2022","unstructured":"Borziak K., Finkelstein J. (2022). X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility. Multiple Sclerosis and Related Disorders, 66(1). https:\/\/doi.org\/10.1016\/j.msard.2022.104065","journal-title":"Multiple Sclerosis and Related Disorders"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2013.03.005"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.07.017"},{"issue":"1","key":"e_1_3_4_10_1","first-page":"151","article-title":"Sexual dimorphism of miRNA expression: A new perspective in understanding the sex bias of autoimmune diseases","volume":"10","author":"Dai R.","year":"2014","unstructured":"Dai R., Ahmed S. (2014). Sexual dimorphism of miRNA expression: A new perspective in understanding the sex bias of autoimmune diseases. Therapeutics and Clinical Risk Management, 10(1), 151\u2013163. https:\/\/doi.org\/10.2147\/TCRM.S33517","journal-title":"Therapeutics and Clinical Risk Management"},{"issue":"1","key":"e_1_3_4_11_1","first-page":"705232","article-title":"Neuroendocrine immunoregulation in multiple sclerosis","volume":"2013","author":"Deckx N.","year":"2013","unstructured":"Deckx N., Lee W. P., Berneman Z., Cools N. (2013). Neuroendocrine immunoregulation in multiple sclerosis. Clinical and Developmental Immunology, 2013(1), 705232. https:\/\/doi.org\/10.1155\/2013\/705232","journal-title":"Clinical and Developmental Immunology"},{"key":"e_1_3_4_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03526-7"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307091111"},{"issue":"1","key":"e_1_3_4_14_1","article-title":"Microbial metabolites in multiple sclerosis: Implication for pathogenesis and treatment","volume":"16","author":"Duarte-Silva E.","year":"2022","unstructured":"Duarte-Silva E., Meuth S., Peixoto C. (2022). Microbial metabolites in multiple sclerosis: Implication for pathogenesis and treatment. Frontiers in Neuroscience, 16(1). https:\/\/doi.org\/10.3389\/fnins.2022.885031","journal-title":"Frontiers in Neuroscience"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0296"},{"issue":"1","key":"e_1_3_4_16_1","first-page":"486282","article-title":"Serum leptin levels in treatment-naive patients with clinically isolated syndrome or relapsing-remitting multiple sclerosi","volume":"2014","author":"Evangelopoulos M.","year":"2014","unstructured":"Evangelopoulos M., Koutsis G., Markianos M. (2014). Serum leptin levels in treatment-naive patients with clinically isolated syndrome or relapsing-remitting multiple sclerosi. Autoimmune Diseases, 2014(1), 486282. https:\/\/doi.org\/10.1155\/2014\/486282","journal-title":"Autoimmune Diseases"},{"issue":"29","key":"e_1_3_4_17_1","first-page":"25","article-title":"Epigenetic mechanisms in multiple sclerosis","volume":"6","author":"Gacias M.","year":"2014","unstructured":"Gacias M., Casaccia P. (2014). Epigenetic mechanisms in multiple sclerosis. Revista Espanola de Esclerosis Multiple, 6(29), 25\u201335.","journal-title":"Revista Espanola de Esclerosis Multiple"},{"key":"e_1_3_4_18_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11142"},{"issue":"11","key":"e_1_3_4_19_1","article-title":"Estrogen signaling in bystander Foxp3neg CD4+ T cells suppress cognate TH17 differentiation in trans and protects from central nervous system autoimmunity.","volume":"201","author":"Garnier L.","year":"2018","unstructured":"Garnier L., Laffont S., L\u00e9lu K., Yogev N., Waisman A., Gu\u00e9ry J. C. (2018). Estrogen signaling in bystander Foxp3neg CD4+ T cells suppress cognate TH17 differentiation in trans and protects from central nervous system autoimmunity. Journal of Immunology, 201(11). https:\/\/doi.org\/10.4049\/jimmunol.1800417","journal-title":"Journal of Immunology"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910072116"},{"key":"e_1_3_4_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-75980-2_4"},{"key":"e_1_3_4_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4441-06.2007"},{"key":"e_1_3_4_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbz036"},{"key":"e_1_3_4_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756285613488434"},{"key":"e_1_3_4_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007961"},{"key":"e_1_3_4_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.01368"},{"key":"e_1_3_4_27_1","doi-asserted-by":"publisher","DOI":"10.1159\/000526895"},{"key":"e_1_3_4_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20522"},{"key":"e_1_3_4_29_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4410"},{"key":"e_1_3_4_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2011.12.003"},{"key":"e_1_3_4_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02600"},{"key":"e_1_3_4_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0109-9"},{"key":"e_1_3_4_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.732694"},{"key":"e_1_3_4_34_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.132"},{"issue":"12","key":"e_1_3_4_35_1","first-page":"6881","article-title":"MiR-1-3p facilitates Th17 differentiation associating with multiple sclerosis via targeting ETS1","volume":"24","author":"Li L.","year":"2020","unstructured":"Li L., Ma X., Zhao Y. F., Zhang C. (2020). MiR-1-3p facilitates Th17 differentiation associating with multiple sclerosis via targeting ETS1. European Review for Medical and Pharmacological Sciences, 24(12), 6881\u20136892. https:\/\/doi.org\/10.26355\/eurrev_202006_21678","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"e_1_3_4_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2020.06.022"},{"key":"e_1_3_4_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000560"},{"key":"e_1_3_4_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000037"},{"key":"e_1_3_4_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101280"},{"key":"e_1_3_4_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2022-328994"},{"key":"e_1_3_4_41_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901351"},{"key":"e_1_3_4_42_1","volume-title":"Bench to bedside: Integrating sex and gender to improve human health","author":"Office of Research on Women\u2019s Health (ORWH)","year":"2022","unstructured":"Office of Research on Women\u2019s Health (ORWH). (2022). Bench to bedside: Integrating sex and gender to improve human health. U.S. Department of Health and Human Services, National Institutes of Health."},{"key":"e_1_3_4_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.995388"},{"key":"e_1_3_4_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annepidem.2011.03.001"},{"issue":"1","key":"e_1_3_4_45_1","first-page":"425","article-title":"The multiple sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities","volume":"8","author":"Parnell G.","year":"2017","unstructured":"Parnell G., Booth D. (2017). The multiple sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities. Frontiers in Immunology, 8(1), 425. https:\/\/doi.org\/10.3389\/fimmu.2017.00425","journal-title":"Frontiers in Immunology"},{"issue":"6460","key":"e_1_3_4_46_1","article-title":"Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility","volume":"365","author":"Patsopoulos A.","year":"2019","unstructured":"Patsopoulos A., Baranzini S. E., Santaniello A., Shoostari P., Cotsapas C., Wong G., Jager P. L. (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science, 365(6460). https:\/\/doi.org\/10.1126\/science.aav7188","journal-title":"Science"},{"key":"e_1_3_4_47_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.4.2227"},{"key":"e_1_3_4_48_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000120"},{"key":"e_1_3_4_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410290514"},{"key":"e_1_3_4_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nrl.2012.10.008"},{"key":"e_1_3_4_51_1","doi-asserted-by":"publisher","DOI":"10.1177\/1971400916666560"},{"key":"e_1_3_4_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009"},{"key":"e_1_3_4_53_1","doi-asserted-by":"publisher","DOI":"10.3109\/08916934.2014.968918"},{"key":"e_1_3_4_54_1","volume-title":"Sex differences in the central nervous system","author":"Shansky R. M.","year":"2015","unstructured":"Shansky R. M. (2015). Sex differences in the central nervous system (Vol. 1). Elsevier Inc."},{"key":"e_1_3_4_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/2042-6410-5-3"},{"key":"e_1_3_4_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40120-017-0086-4"},{"key":"e_1_3_4_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2015.06.015"},{"key":"e_1_3_4_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.470"},{"issue":"3","key":"e_1_3_4_59_1","first-page":"629","article-title":"One hundred years of linkage disequilibrium","volume":"209","author":"Sved J.","year":"2018","unstructured":"Sved J., Hill W. (2018). One hundred years of linkage disequilibrium. Genetics, 209(3), 629\u2013636. https:\/\/doi.org\/10.1534\/genetics.118.300642","journal-title":"Genetics"},{"key":"e_1_3_4_60_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2003.033324"},{"key":"e_1_3_4_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2007.02690.x"},{"key":"e_1_3_4_62_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031579"},{"key":"e_1_3_4_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/2042-6410-2-1"},{"key":"e_1_3_4_64_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458519892491"},{"key":"e_1_3_4_65_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517737394"},{"key":"e_1_3_4_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2009.08.056"},{"key":"e_1_3_4_67_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-08-1323"},{"key":"e_1_3_4_68_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/675851"},{"key":"e_1_3_4_69_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13004"},{"key":"e_1_3_4_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.766308"},{"key":"e_1_3_4_71_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00060.2017"},{"key":"e_1_3_4_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.10.002"},{"key":"e_1_3_4_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2025.102592"}],"container-title":["Biological Research For Nursing"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10998004251387318","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10998004251387318","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10998004251387318","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:39:03Z","timestamp":1777383543000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10998004251387318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":72,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1177\/10998004251387318"],"URL":"https:\/\/doi.org\/10.1177\/10998004251387318","relation":{},"ISSN":["1099-8004","1552-4175"],"issn-type":[{"value":"1099-8004","type":"print"},{"value":"1552-4175","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]}}}