{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:59:52Z","timestamp":1791197992220,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Biological sex is routinely incorporated into systemic sclerosis (SSc) research as a demographic or stratification variable. Women are substantially more likely to develop SSc, whereas men experience a greater burden of severe organ involvement and adverse outcomes. Whether these observations represent parallel sex-associated differences or reflect differences in the relationships among disease components remains unresolved. Here, we propose the Systemic Sclerosis\u2013Multilayer Architecture Framework (SSc-MAF) as a hypothesis-generating framework for addressing this distinction. We define a sex-dependent architectural difference not as an isolated difference in a molecule, cell population, pathway, or clinical phenotype, but as a reproducible sex-associated difference in relationships among disease components, including multicellular communication, fibrovascular coupling, spatial tissue organization, molecular co-activation, or longitudinal clinical\u2013biological trajectories. SSc-MAF therefore distinguishes clinical disease trajectories from the biological architecture that may generate them and from the methodological strategies required for empirical validation. We critically evaluate current evidence across immune, fibrovascular, metabolic, and regulatory domains, while distinguishing direct sex-stratified SSc evidence from indirect mechanistic evidence and framework-level hypotheses. We further outline measurable predictions and conditions that would weaken or fail to support individual propositions of SSc-MAF. This framework is intended not to establish sex-dependent disease architecture as a proven feature of SSc, but to provide an operational strategy for testing whether biological sex contributes information beyond conventional component-level comparisons and additive covariate adjustment.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1978654","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:05:06Z","timestamp":1791194706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Biological sex and disease architecture in systemic sclerosis: a multilayer translational framework for precision medicine"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi\u2019an","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, The Affiliated Huai\u2019an No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huai\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neonatology, The Affiliated Huai\u2019an No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huai\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s12016-025-09062-1","article-title":"Sex bias in systemic sclerosis: from clinical to immunological differences","volume":"68","author":"Sakkas","year":"2025","journal-title":"Clin Rev Allergy Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X251384602","article-title":"Sex differences in systemic sclerosis: from pathogenesis to clinical manifestations and treatment","volume":"17","author":"Toitou","year":"2025","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.140006","article-title":"The effect of male sex on survival in systemic sclerosis","volume":"41","author":"Hussein","year":"2014","journal-title":"J Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.114264","article-title":"Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research group database","volume":"69","author":"Tyndall","year":"2010","journal-title":"Ann Rheum Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/art.40027","article-title":"Early mortality in a multinational systemic sclerosis inception cohort","volume":"69","author":"Hao","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00376-5","article-title":"Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study","volume":"8","author":"Rodriguez-Martin","year":"2026","journal-title":"Lancet Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4384","DOI":"10.1038\/s41467-021-24607-6","article-title":"Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin","volume":"12","author":"Tabib","year":"2021","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224184","article-title":"Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups","volume":"82","author":"Clark","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4949","DOI":"10.1038\/s41467-025-60034-7","article-title":"Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis","volume":"16","author":"Shimagami","year":"2025","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323299","article-title":"Characterization of vascular niche in systemic sclerosis by spatial proteomics","volume":"134","author":"Rius Rigau","year":"2024","journal-title":"Circ Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.04.025","article-title":"Spatial multiomics decipher fibroblast-macrophage dynamics in systemic sclerosis","volume":"84","author":"Li","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s41467-023-44645-6","article-title":"Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis","volume":"15","author":"Ma","year":"2024","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljae286","article-title":"Atypical chemokine receptor 1-positive endothelial cells mediate leucocyte infiltration and synergize with secreted frizzled-related protein 2\/asporin-positive fibroblasts to promote skin fibrosis in systemic sclerosis","volume":"191","author":"Huang","year":"2024","journal-title":"Br J Dermatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.06.002","article-title":"Spatially informed phenotyping by cyclic-in-situ-hybridisation identifies novel fibroblast populations and their pathogenic niches in systemic sclerosis","volume":"84","author":"Li","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(22)00193-X","article-title":"Sex differences in clinical outcomes and biological profiles in systemic sclerosis-associated interstitial lung disease: a post-hoc analysis of two randomised controlled trials","volume":"4","author":"Volkmann","year":"2022","journal-title":"Lancet Rheumatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kead234","article-title":"Prognostic and predictive markers of systemic sclerosis-associated interstitial lung disease in a clinical trial and long-term observational cohort","volume":"63","author":"Ghuman","year":"2024","journal-title":"Rheumatol (Oxford)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac660","article-title":"Sex influence on outcomes of patients with systemic sclerosis-associated interstitial lung disease: a EUSTAR database analysis","volume":"62","author":"Campochiaro","year":"2023","journal-title":"Rheumatol (Oxford)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae639","article-title":"Pulmonary involvement in systemic sclerosis: can sex play a role","volume":"64","author":"Koletsos","year":"2025","journal-title":"Rheumatol (Oxford)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12890-024-03474-z","article-title":"An exploratory analysis of differences in serum protein expression by sex in patients with systemic sclerosis associated interstitial lung disease","volume":"25","author":"Cerro-Chiang","year":"2025","journal-title":"BMC Pulm Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22121","article-title":"Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the PHAROS registry","volume":"66","author":"Chung","year":"2014","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-0933-1","article-title":"Sex disparities in systemic sclerosis-associated pulmonary arterial hypertension: a cohort study","volume":"18","author":"Pasarikovski","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms27104363","article-title":"Sex disparity in systemic sclerosis-associated pulmonary fibrosis","volume":"27","author":"Galimba","year":"2026","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/art.21026","article-title":"Skewed X chromosome inactivation in blood cells of women with scleroderma","volume":"52","author":"Ozbalkan","year":"2005","journal-title":"Arthritis Rheum"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231809","article-title":"Altered X-chromosome inactivation of the TLR7\/8 locus and heterogeneity of pDCs in systemic sclerosis","volume":"222","author":"Du","year":"2025","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aap8855","article-title":"TLR7 escapes X chromosome inactivation in immune cells","volume":"3","author":"Souyris","year":"2018","journal-title":"Sci Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/art.27224","article-title":"Systemic sclerosis and lupus: points in an interferon-mediated continuum","volume":"62","author":"Assassi","year":"2010","journal-title":"Arthritis Rheum"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1114576","article-title":"Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis","volume":"370","author":"van Bon","year":"2014","journal-title":"N Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/25785826.2024.2360690","article-title":"Single cell analysis in systemic sclerosis\u2014a systematic review","volume":"47","author":"Fukasawa","year":"2024","journal-title":"Immunol Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljaf444","article-title":"CCL19+ fibroblast-CCR7+ T-cell crosstalk coordinates immunofibrotic signalling networks in systemic sclerosis","volume":"194","author":"Guo","year":"2026","journal-title":"Br J Dermatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/art.37988","article-title":"Evidence that systemic sclerosis is a vascular disease","volume":"65","author":"Matucci-Cerinic","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.198954","article-title":"Multimodal analyses of early, untreated systemic sclerosis skin identify a proinflammatory vascular niche of macrophage-fibroblast signaling","volume":"11","author":"Jarnagin","year":"2026","journal-title":"JCI Insight"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.10.033","article-title":"RUNX1 is expressed in a subpopulation of dermal fibroblasts and is associated with disease severity of systemic sclerosis","volume":"85","author":"Parvizi","year":"2026","journal-title":"Ann Rheum Dis"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-205303","article-title":"Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies","volume":"74","author":"Altorok","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/art.41694","article-title":"Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin","volume":"73","author":"Tsou","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.005","article-title":"Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization","volume":"42","author":"Jha","year":"2015","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2019.07.007","article-title":"Sex hormones and sex hormone-targeting therapies in systemic sclerosis: a systematic literature review","volume":"50","author":"Ciaffi","year":"2020","journal-title":"Semin Arthritis Rheum"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.326.7382.219","article-title":"Interaction revisited: the difference between two estimates","volume":"326","author":"Altman","year":"2003","journal-title":"BMJ"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2016.9125","article-title":"Evaluation of evidence of statistical support and corroboration of subgroup claims in randomized clinical trials","volume":"177","author":"Wallach","year":"2017","journal-title":"JAMA Intern Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3224","DOI":"10.1038\/s41467-022-30755-0","article-title":"Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data","volume":"13","author":"Dimitrov","year":"2022","journal-title":"Nat Commun"},{"key":"B42","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/nrg.2018.4","article-title":"Integrative omics for health and disease","volume":"19","author":"Karczewski","year":"2018","journal-title":"Nat Rev Genet"},{"key":"B43","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13059-020-02015-1","article-title":"MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data","volume":"21","author":"Argelaguet","year":"2020","journal-title":"Genome Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01981-2","article-title":"Multimodal biomedical AI","volume":"28","author":"Acosta","year":"2022","journal-title":"Nat Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1186\/s13075-020-02323-8","article-title":"Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation\u2014a prospective, observational study","volume":"22","author":"Andr\u00e9asson","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae394","article-title":"The 2024 British Society for Rheumatology guideline for management of systemic sclerosis","volume":"63","author":"Denton","year":"2024","journal-title":"Rheumatol (Oxford)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae390","article-title":"The 2024 British Society for Rheumatology guideline for management of systemic sclerosis\u2014executive summary","volume":"63","author":"Denton","year":"2024","journal-title":"Rheumatol (Oxford)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1978654\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:05:07Z","timestamp":1791194707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1978654\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2026.1978654"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1978654","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"1978654"}}