Pathogenic autoantibody internalization in myositis.

Autor:	Pinal-Fernandez I; Muscle 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., Muñoz-Braceras S; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Casal-Dominguez M; Muscle 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., Pak K; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Torres-Ruiz J; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.; Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Musai J; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Dell'Orso S; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Naz F; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Islam S; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Gutierrez-Cruz G; Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Cano MD; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain., Matas-Garcia A; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.; Barcelona University, Barcelona, Spain.; CIBERER and IDIBAPS, Barcelona, Spain., Padrosa J; CIBERER and IDIBAPS, Barcelona, Spain., Tobías-Baraja E; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.; Barcelona University, Barcelona, Spain.; CIBERER and IDIBAPS, Barcelona, Spain., Garrabou G; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.; Barcelona University, Barcelona, Spain.; CIBERER and IDIBAPS, Barcelona, Spain., Aldecoa I; Pathology, Neurological Tissue Bank. Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain., Espinosa G; Barcelona University, 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 Clinic, Barcelona, Spain., Simeon-Aznar CP; Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.; Autonomous University of Barcelona, Barcelona, Spain., Guillen-Del-Castillo A; Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.; Autonomous University of Barcelona, Barcelona, Spain., Gil-Vila A; Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.; Autonomous University of Barcelona, Barcelona, Spain., Trallero-Araguas E; Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.; Autonomous University of Barcelona, Barcelona, Spain., Christopher-Stine L; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Lloyd TE; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Liewluck T; Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA., Naddaf E; Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA., Stenzel W; Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany., Greenberg SA; Department of Neurology, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, MA, USA., Grau JM; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.; Barcelona University, Barcelona, Spain.; CIBERER and IDIBAPS, Barcelona, Spain., Selva-O'Callaghan A; Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain.; Autonomous University of Barcelona, Barcelona, Spain., Milisenda JC; Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain.; Barcelona University, Barcelona, Spain.; CIBERER and IDIBAPS, Barcelona, Spain., Mammen AL; Muscle 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.; Autonomous University of Barcelona, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jan 17. Date of Electronic Publication: 2024 Jan 17.
DOI:	10.1101/2024.01.15.24301339
Abstrakt:	Objectives: Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins. Methods: Confocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing. Results: In patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis. Conclusions: In myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease. Competing Interests: Competing interests: None.
Databáze:	MEDLINE
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