Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies

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 <i>in vitro</i>. 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-ß1 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.

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Publication Details

Journal
medRxiv
Published
2026-02-17
DOI
https://doi.org/10.64898/2026.02.14.26346329
Primary Topic
Inflammatory Myopathies and Dermatomyositis
Type
article
Field-Weighted Citation Impact
0.00

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article

Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies

Sandra Muñoz-Braceras, E. Trallero, Aster Kenea, Benjamin Ellezam et al.
medRxiv
Inflammatory Myopathies and Dermatomyositis
article

Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies

Sandra Muñoz-Braceras, E. Trallero, Aster Kenea, Benjamin Ellezam, Werner Stenzel, Gustaf Wigerblad, Stefania Dell’Orso, Travis B. Kinder, Yves Troyanov, Ana Matas-García, Alain Meyer, Valentine Gilbart, Albert Gil-Vila, Andreu Fernández-Codina, Iban Aldecoa, Katherine Pak, Corinna Preusse, Gilles Laverny, Davide Randazzo, Faiza Naz, Elie Naddaf, Shamima Islam, Gabriela Ailen-Caballero, Felix Kleefeld, Iago Pinal-Fernandez, Nikolas Bublitz, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Gerard Espinosa, S. Amara Ogbonnaya-Whittlesey, Gloria Garrabou, Marie Hudson, Océane Landon-Cardinal, Janet E. Pope, Andrew L. Mammen, Jose C. Milisenda, Albert Selva-O’Callaghan
article en

Abstract

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 <i>in vitro</i>. 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-ß1 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.

medRxiv
Hebron University (PS), Universitat Autònoma de Barcelona (ES), Western University (CA), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Mayo Clinic (US), Johns Hopkins University (US), Inserm (FR), Universität Hamburg (DE), Johns Hopkins Medicine (US), Jewish General Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), WinnMed (US), Humboldt-Universität zu Berlin (DE), Office of Science (US), Institut de génétique et de biologie moléculaire et cellulaire (FR), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Autoimmune Technologies (United States) (US), University Medical Center Hamburg-Eppendorf (DE), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Clínic de Barcelona (ES), Vall d'Hebron Hospital Universitari (ES), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Hôpital du Sacré-Cœur de Montréal (CA), Centre Hospitalier de l’Université de Montréal (CA), Hôpitaux Universitaires de Strasbourg (FR), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Université de Strasbourg (FR), Universitat de Barcelona (ES)
Agence Nationale de la Recherche, Université de Montréal, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Good health and well-being
Openalex Percentile: Top 51%
Inflammatory Myopathies and Dermatomyositis
DOIOpen Access PDFOpenAlex
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