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Myositis
Pathological autoantibody internalisation in myositis
  1. Iago Pinal-Fernandez1,2,
  2. Sandra Muñoz-Braceras1,
  3. Maria Casal-Dominguez1,2,
  4. Katherine Pak1,
  5. Jiram Torres-Ruiz1,3,
  6. Jon Musai1,
  7. Stefania Dell'Orso1,
  8. Faiza Naz1,
  9. Shamima Islam1,
  10. Gustavo Gutierrez-Cruz1,
  11. Maria Dolores Cano4,
  12. Ana Matas-Garcia4,5,6,
  13. Joan Padrosa6,
  14. Ester Tobias-Baraja4,5,6,
  15. Gloria Garrabou4,5,6,
  16. Iban Aldecoa7,
  17. Gerard Espinosa5,8,
  18. Carmen Pilar Simeon-Aznar9,10,
  19. Alfredo Guillen-Del-Castillo9,10,
  20. Albert Gil-Vila9,10,
  21. Ernesto Trallero-Araguás9,10,11,
  22. Lisa Christopher-Stine2,12,
  23. Thomas E Lloyd2,
  24. Teerin Liewluck13,
  25. Elie Naddaf13,
  26. Werner Stenzel14,
  27. Steven A Greenberg15,
  28. Josep Maria Grau4,5,6,
  29. Albert Selva-O’Callaghan9,10,
  30. Jose Cesar Milisenda4,5,6,
  31. Andrew Lee Mammen1,2,12
  1. 1Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  4. 4Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
  5. 5Barcelona University, Barcelona, Spain
  6. 6CIBERER and IDIBAPS, Barcelona, Spain
  7. 7Pathology, Neurological Tissue Bank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain
  8. 8Department 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
  9. 9Systemic Autoimmune Disease Section, Vall d’Hebron Institute of Research, Barcelona, Spain
  10. 10Autonomous University of Barcelona, Barcelona, Spain
  11. 11Rheumatology Department, Vall d’Hebron Hospital, Barcelona, Spain
  12. 12Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  13. 13Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  14. 14Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
  15. 15Department of Neurology, Brigham and Women’s Hospital and Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Andrew Lee Mammen, National Institutes of Health, Bethesda, Maryland, USA; andrew.mammen{at}nih.gov; Dr Iago Pinal-Fernandez; iago.pinalfernandez{at}nih.gov

Abstract

Objectives Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption.

Methods Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing.

Results In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets.

Conclusions This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.

  • Autoantibodies
  • Dermatomyositis
  • Polymyositis
  • Antibodies

Data availability statement

Data are available on reasonable request. Any anonymised data not published within the article will be shared by request from any qualified investigator.

https://doi.org/10.1136/ard-2024-225773

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    Data availability statement

    Data are available on reasonable request. Any anonymised data not published within the article will be shared by request from any qualified investigator.

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    Footnotes

    • IP-F and SM-B are joint first authors.

    • JCM and ALM are joint senior authors.

    • Handling editor Josef S Smolen

    • X @DrIagoPinal, @gerardespinosa5, @elienaddaf3

    • MC-D, KP and JT-R contributed equally.

    • Deceased Dr. Josep Maria Grau passed away while this manuscript was under review.

    • Contributors All authors contributed to the development of the manuscript, including interpretation of results, substantive review of drafts and approval of the final draft for submission. IP-F and ALM are the guarantors.

    • Funding This study was funded, in part, by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.