{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:28:07Z","timestamp":1785432487769,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,14]]},"group-title":"Immunology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R21-AR081588"],"award-info":[{"award-number":["R21-AR081588"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Penn Colton Center for Autoimmunity and the Institute for Immunology and Immune Health","award":["I3H Pilot Award"],"award-info":[{"award-number":["I3H Pilot Award"]}]},{"award":["Scientist Development Award"],"award-info":[{"award-number":["Scientist Development Award"]}],"id":[{"id":"https:\/\/ror.org\/03sdr0263","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Postdoctoral Fellowship"],"award-info":[{"award-number":["Postdoctoral Fellowship"]}],"id":[{"id":"https:\/\/ror.org\/00zyvrn45","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Division of Rheumatology, University of Pennsylvania","award":["H. Ralph Schumacher Rheumatology Research Fund"],"award-info":[{"award-number":["H. Ralph Schumacher Rheumatology Research Fund"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Systemic sclerosis (SSc) predominantly affects females but exhibits greater disease severity in males, suggesting sex differences underlying SSc pathogenesis. We sought to define sex-associated alterations in the peripheral immune landscape of patients with SSc.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed high-dimensional immune profiling of PBMCs from 37 healthy donors (68% female) and 37 patients with SSc (11 limited, 26 diffuse; 68% female) using 30-color spectral flow cytometry, quantifying 56 immune cell subsets per donor. We conducted sex-stratified comparisons and correlation analysis, and used principal component analysis followed by linear discriminant analysis to derive a sex-discriminant immune cellular module.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Diffuse cutaneous SSc (dcSSc) was associated with a distinct immune landscape characterized by increased monocyte and decreased natural killer-like and B cell frequencies, suggesting a myeloid-skewed peripheral immunophenotype. Males exhibited greater enrichment of innate immune subsets, including monocyte and dendritic cell subsets, while females exhibited greater enrichment of adaptive immune subsets. Among T cells, dcSSc was associated with coordinated remodeling across CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    subsets, including expansion of stem cell memory T cells (Tscm), and increased regulatory T cells, Th17 skewing, and decreased effector-memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    subsets. Females exhibited greater proportions of na\u00efve- and Tscm, and males exhibited higher proportions of effector-memory subsets. Integrating these data, we identified a sex-discriminant immune module comprised of 20 cell types that distinguishes males and females with dcSSc.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>SSc is associated with sex-specific differences in the peripheral immune landscape. A sex-associated immune program, further amplified in disease, may contribute to the paradox of female-biased susceptibility and male-biased severity in SSc.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.11.724091","type":"posted-content","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:40:13Z","timestamp":1778787613000},"source":"Crossref","is-referenced-by-count":0,"title":["Deep immune profiling of the peripheral blood reveals disease- and sex-associated immune cell signatures in patients with systemic sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-1767","authenticated-orcid":false,"given":"Nikhil","family":"Jiwrajka","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104"},{"name":"Division of Rheumatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin","family":"Tuluc","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Laboratory, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6091-6043","authenticated-orcid":false,"given":"Nuriban","family":"Valero-Pacheco","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer B.","family":"Murray","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Laboratory, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-4291","authenticated-orcid":false,"given":"Sylvia E.","family":"Posso","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, 98101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":false,"given":"Jane H.","family":"Buckner","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, 98101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4992-3079","authenticated-orcid":false,"given":"Montserrat C.","family":"Anguera","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051801101155000_2026.05.11.724091v1.1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212477"},{"key":"2026051801101155000_2026.05.11.724091v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2019.09.012"},{"key":"2026051801101155000_2026.05.11.724091v1.3","doi-asserted-by":"crossref","first-page":"e668","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","year":"2022","journal-title":"The Lancet Rheumatology"},{"key":"2026051801101155000_2026.05.11.724091v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/art.22375"},{"key":"2026051801101155000_2026.05.11.724091v1.5","doi-asserted-by":"crossref","first-page":"1168645","DOI":"10.3389\/fdmed.2023.1168645","article-title":"Sex-specific differences in primary Sj\u00f6gren\u2019s disease","volume":"4","year":"2023","journal-title":"Front Dent Med"},{"key":"2026051801101155000_2026.05.11.724091v1.6","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1093\/mr\/roac091","article-title":"Differences in sex- and age-associated mortality in patients with anti-MDA5-positive dermatomyositis","volume":"33","year":"2023","journal-title":"Mod Rheumatol"},{"key":"2026051801101155000_2026.05.11.724091v1.7","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s10067-023-06816-0","article-title":"Gender differences in patients with anti-MDA5-positive dermatomyositis: a cohort study of 251 cases","volume":"43","year":"2024","journal-title":"Clin Rheumatol"},{"key":"2026051801101155000_2026.05.11.724091v1.8","doi-asserted-by":"crossref","unstructured":"Hughes, M. et al. 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