Evidence map›Paper›PMID 42493309›Full record

ArticleAnnals of the rheumatic diseases2026

Spatial transcriptomics reveals mechanism of autoimmunity driven by internalised autoantibodies.

Iago Pinal-Fernandez, Katherine Pak, Maria Casal-Dominguez, Sandra Muñoz-Braceras, Gustaf Wigerblad, Stefania Dell'Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Travis B Kinder and 32 more

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Article in Annals of the rheumatic diseases, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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42 authors.

Iago Pinal-FernandezMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: iago.pinalfernandez@nih.gov.
Katherine PakMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Maria Casal-DominguezMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sandra Muñoz-BracerasMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Gustaf WigerbladGenomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Stefania Dell'OrsoGenomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Faiza NazGenomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Shamima IslamGenomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Gustavo Gutierrez-CruzGenomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Travis B KinderMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
S Amara Ogbonnaya-WhittleseyMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Andreu Fernández-CodinaDivision of Rheumatology, Western University, London, ON, Canada; Division of General Internal Medicine, Windsor Campus, Western University, London, ON, Canada; Division of Rheumatology, Rheumatology Research Group, Vall d'Hebron University Hospital, Barcelona, Spain.
Margherita GianniniExplorations Fonctionnelles Musculaires, Centre de Référence Des Maladies Autoimmunes Rares, Centre de Recherche en Biomédecine de Strasbourg, Rhumatologie, Hôpitaux Universitaires de Strasbourg, UR 3072, Université de Strasbourg, Strasbourg, France.
Benjamin EllezamDivision of Pathology, CHU Sainte-Justine, Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada.
Gilles LavernyUniversité de Strasbourg, CNRS, Inserm, IGBMC UMR 7104- UMR-S 1258, F-67400 Illkirch, France.
Valentine GilbartUniversité de Strasbourg, CNRS, Inserm, IGBMC UMR 7104- UMR-S 1258, F-67400 Illkirch, France.
Océane Landon-CardinalDivision of Rheumatology, Centre hospitalier de l'Université de Montréal (CHUM), Autoimmunity Research Laboratory, CHUM Research Center, Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Marie HudsonDivision of Rheumatology, Department of Medicine, Jewish General Hospital, Lady Davis Institute and McGill University, Montreal, QC, Canada.
Yves TroyanovDivision of Rheumatology, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Davide RandazzoLight Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Aster KeneaLight Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Ana Matas-GarciaMuscle Research Unit, Internal Medicine Service, Hospital Clinic, IDIBAPS, CIBER, UB, Barcelona, Spain; University of Barcelona, Barcelona, Spain; CIBERER and IDIBAPS, Barcelona, Spain.
Gloria GarrabouMuscle Research Unit, Internal Medicine Service, Hospital Clinic, IDIBAPS, CIBER, UB, Barcelona, Spain; University of Barcelona, Barcelona, Spain; CIBERER and IDIBAPS, Barcelona, Spain.
Iban AldecoaPathology Department and Neurological Tissue Bank of the Biobank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain.
Gabriela Ailen-CaballeroPathology Department and Neurological Tissue Bank of the Biobank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain.
Albert Gil-VilaSystemic Autoimmune Disease Section, Division of Internal Medicine Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.
Ernesto TralleroDivision of Rheumatology, Rheumatology Research Group, Vall d'Hebron University Hospital, Barcelona, Spain; Systemic Autoimmune Disease Section, Division of Internal Medicine Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.
Margherita MiloneDivision of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Teerin LiewluckDivision of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Elie NaddafDivision of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Gerard EspinosaUniversity of Barcelona, Barcelona, Spain; Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems, Member of ERN-ReCONNET, Hospital Clínic, Barcelona, Spain.
Carmen Pilar Simeon-AznarSystemic Autoimmune Disease Section, Division of Internal Medicine Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.
Alfredo Guillen-Del-CastilloSystemic Autoimmune Disease Section, Division of Internal Medicine Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.
Corinna PreusseCharité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neuropathology, Berlin, Germany.
Felix KleefeldCharité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neurology, Berlin, Germany.
Nikolas BublitzDivision of Rheumatology and Systemic Inflammatory Diseases, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Werner StenzelCharité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neuropathology, Berlin, Germany.
Alain MeyerExplorations Fonctionnelles Musculaires, Centre de Référence Des Maladies Autoimmunes Rares, Centre de Recherche en Biomédecine de Strasbourg, Rhumatologie, Hôpitaux Universitaires de Strasbourg, UR 3072, Université de Strasbourg, Strasbourg, France.
Janet E PopeDivision of Rheumatology, Western University, London, ON, Canada.
Albert Selva-O'CallaghanSystemic Autoimmune Disease Section, Division of Internal Medicine Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.
Jose C MilisendaMuscle Research Unit, Internal Medicine Service, Hospital Clinic, IDIBAPS, CIBER, UB, Barcelona, Spain; University of Barcelona, Barcelona, Spain; CIBERER and IDIBAPS, Barcelona, Spain.
Andrew L MammenMuscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: andrew.mammen@nih.gov.

Funding

Intramural NIH HHS Z99 AR999999
6 · The paper itself

Abstract

objectivesAutoantibody internalisation has been implicated in autoimmune disease pathogenesis, yet its mechanisms and generalisability across diseases, cell types, and tissues remain poorly defined. We sought to address these gaps.

methodsBulk RNA sequencing was performed on 814 muscle biopsies from patients with autoimmune diseases and healthy controls, including an external validation cohort of 41 additional samples. Purified patient immunoglobulin (Ig) G was electroporated into primary human cells to assess functional effects in vitro. Immunofluorescence evaluated localisation of immunoglobulins across diseases and tissues. Spatial transcriptomics assessed disease-specific gene expression, cellular injury, and inflammatory responses.

resultsUsing anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis as model diseases, we validated reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction across cohorts and confirmed that electroporation of purified patient IgG into healthy primary cells recapitulates these disease-associated transcriptional programmes. Spatial transcriptomics linked these signatures to cellular injury and distinct inflammatory responses, including activation of type I interferon and TGFβ signalling in anti-Mi2 dermatomyositis and type II interferon signalling in anti-PM/Scl scleromyositis. These programmes were observed predominantly not only in muscle fibres but also in macrophages, endothelial cells, and fibroblasts/fibroadipogenic progenitors. Spatial transcriptomics further revealed transfer of immunoglobulin RNA from antibody-secreting cells to adjacent target cells expressing disease-specific transcriptional programmes. Antibody internalisation, previously described in myositis muscle, was also observed in skin from patients with anti-Mi2 and anti-PM/Scl and in tissues from anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis.

conclusionsTogether, these findings establish autoantibody internalisation as a mechanism of tissue injury in autoimmunity, suggesting its broader relevance across autoantibody-mediated diseases.

Identifiers

PMID42493309
PMCPMC13454472

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