Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies
Year: 2026
Type: preprint
Abstract: 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 in vitro . 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.
Source: medRxiv
Authors: 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, S. Amara Ogbonnaya-Whittlesey, Andreu Fernández-Codina, Margherita Giannini, Benjamin Ellezam, Gilles Laverny, Valentine Gilbart, Océane Landon-Cardinal, Marie Hudson, Yves Troyanov, Davide Randazzo, Aster Kenea, Ana Matas-Garcia, Gloria Garrabou, Iban Aldecoa, Gabriela Ailen-Caballero, Albert Gil-Vila, Ernesto Trallero, Margherita Milone, Teerin Liewluck, Elie Naddaf, Gerard Espinosa, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Corinna Preusse, Felix Kleefeld, Nikolas Bublitz, Werner Stenzel, Alain Meyer, Janet E. Pope, Albert Selva-O’Callaghan, Jose C. Milisenda, Andrew L. Mammen
Institutions: National Institutes of Health, Johns Hopkins University, Johns Hopkins Medicine, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Western University, Vall d'Hebron Hospital Universitari, Hôpitaux Universitaires de Strasbourg, Mitochondrie, stress oxydant et protection musculaire, Université de Strasbourg, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Centre Hospitalier de l’Université de Montréal, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Hôpital du Sacré-Cœur de Montréal, Centre for Biomedical Network Research on Rare Diseases, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Fundació Clínic per a la Recerca Biomèdica, Universitat Autònoma de Barcelona, Mayo Clinic, ERN ReCONNET, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Charité - Universitätsmedizin Berlin, University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7129703208