{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T03:29:17Z","timestamp":1787887757718,"version":"build-2784847793"},"posted":{"date-parts":[[2026,2,17]]},"group-title":"Rheumatology","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM\/Scl scleromyositis across independent cohorts. Electroporation of purified patient IgG into primary cultures of healthy cells was sufficient to induce the corresponding transcriptomic programs\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Direct immunofluorescence demonstrated immunoglobulin internalization into subcellular compartments matching the localization of the autoantigen in different affected tissues. Spatial transcriptomic analyses revealed that antibody-secreting cells translocated cytoplasmic material (i.e., immunoglobulin RNA) into adjacent affected cells expressing autoantibody-specific transcripts. The disease-specific transcripts were present not only in muscle fibers, but also in other cells, including macrophages, endothelial cells, and fibroblasts. Autoantibody-induced transcriptomic programs were associated with cell damage and autoantibody-specific reactive inflammatory programs, including activation of type I interferon and TGF-\u00df1 signaling in anti-Mi2 dermatomyositis and activation of type II interferon in anti-PM\/Scl scleromyositis. Antibody internalization was also observed in different tissues from patients with other autoimmune diseases, including anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. Together, these findings establish autoantibody internalization as a shared pathogenic mechanism across diverse autoimmune diseases, providing a unifying framework for conditions driven by autoantibodies against intracellular antigens.\n                <\/jats:p>","DOI":"10.64898\/2026.02.14.26346329","type":"posted-content","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T15:50:18Z","timestamp":1771343418000},"source":"Crossref","is-referenced-by-count":2,"title":["Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6338-9218","authenticated-orcid":false,"given":"Iago","family":"Pinal-Fernandez","sequence":"first","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Pak","sequence":"additional","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Casal-Dominguez","sequence":"additional","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Mu\u00f1oz-Braceras","sequence":"additional","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustaf","family":"Wigerblad","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Dell\u2019Orso","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiza","family":"Naz","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamima","family":"Islam","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Gutierrez-Cruz","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis B.","family":"Kinder","sequence":"additional","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Amara","family":"Ogbonnaya-Whittlesey","sequence":"additional","affiliation":[{"name":"Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreu","family":"Fern\u00e1ndez-Codina","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Western University, London, ON, Canada"},{"name":"Division of General Internal Medicine, Windsor Campus, Western University, London, ON, Canada"},{"name":"Division of Rheumatology, Rheumatology Research Group, Vall d\u2019Hebron University Hospital, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-5804","authenticated-orcid":false,"given":"Margherita","family":"Giannini","sequence":"additional","affiliation":[{"name":"Explorations Fonctionnelles Musculaires, Centre de R\u00e9f\u00e9rence Des Maladies Autoimmunes Rares, Centre de Recherche en Biom\u00e9decine de Strasbourg, Rhumatologie, H\u00f4pitaux Universitaires de Strasbourg, UR 3072, Universit\u00e9 de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8716-7924","authenticated-orcid":false,"given":"Benjamin","family":"Ellezam","sequence":"additional","affiliation":[{"name":"Division of Pathology, CHU Sainte-Justine, Department of Pathology and Cell Biology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Laverny","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, Inserm, IGBMC UMR 7104-UMR-S 1258, F-67400 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentine","family":"Gilbart","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, Inserm, IGBMC UMR 7104-UMR-S 1258, F-67400 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oc\u00e9ane","family":"Landon-Cardinal","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Centre hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CHUM), Autoimmunity Research Laboratory, CHUM Research Center, Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Hudson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, Jewish General Hospital, Lady Davis Institute and McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Troyanov","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, H\u00f4pital du Sacr\u00e9-C\u0153ur de Montr\u00e9al; Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Randazzo","sequence":"additional","affiliation":[{"name":"Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aster","family":"Kenea","sequence":"additional","affiliation":[{"name":"Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Matas-Garcia","sequence":"additional","affiliation":[{"name":"Muscle Research Unit, Internal Medicine Service, Hospital Clinic, IDIBAPS, CIBER, UB, Barcelona, Spain"},{"name":"University of Barcelona, Barcelona, Spain"},{"name":"CIBERER and IDIBAPS, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Garrabou","sequence":"additional","affiliation":[{"name":"Muscle Research Unit, Internal Medicine Service, Hospital Clinic, IDIBAPS, CIBER, UB, Barcelona, Spain"},{"name":"University of Barcelona, Barcelona, Spain"},{"name":"CIBERER and IDIBAPS, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iban","family":"Aldecoa","sequence":"additional","affiliation":[{"name":"Pathology Department and Neurological Tissue Bank of the Biobank. 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