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Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies
  1. Iago Pinal-Fernandez1,2,
  2. Jose Cesar Milisenda1,3,4,5,
  3. Katherine Pak1,
  4. Sandra Muñoz-Braceras1,
  5. Maria Casal-Dominguez1,
  6. Jiram Torres-Ruiz1,6,
  7. Stefania Dell'Orso1,
  8. Faiza Naz1,
  9. Gustavo Gutierrez-Cruz1,
  10. Yaiza Duque-Jaimez3,
  11. Ana Matas-Garcia3,4,5,
  12. Joan Padrosa5,
  13. Francesc J Garcia-Garcia3,4,5,
  14. Mariona Guitart-Mampel3,4,5,
  15. Gloria Garrabou3,4,5,
  16. Ernesto Trallero-Araguás7,
  17. Brian Walitt8,
  18. Julie J Paik9,
  19. Jemima Albayda9,
  20. Lisa Christopher-Stine2,9,
  21. Thomas E Lloyd2,
  22. Josep Maria Grau-Junyent3,4,5,
  23. Albert Selva-O'Callaghan10,11,
  24. Andrew Lee Mammen1,2,9
  1. 1 Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  2. 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
  4. 4 Barcelona University, Barcelona, Spain
  5. 5 CIBERER, Barcelona, Spain
  6. 6 Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  7. 7 Rheumatology Department, Vall d’Hebron Hospital, Barcelona, Spain
  8. 8 National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA
  9. 9 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  10. 10 Systemic Autoimmune Disease Unit, Vall d’Hebron Institute of Research, Barcelona, Spain
  11. 11 Autonomous University of Barcelona, Barcelona, Spain
  1. Correspondence to Dr Iago Pinal-Fernandez, National Institutes of Health, Bethesda, USA; iago.pinalfernandez{at}nih.gov; Dr Andrew Lee Mammen; andrew.mammen{at}nih.gov

Abstract

Objectives Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.

Methods RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.

Results A set of 135 genes, including SCRT1 and MADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei.

Conclusions Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

  • dermatomyositis
  • autoimmunity
  • inflammation
  • polymyositis

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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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

  • Handling editor Josef S Smolen

  • Twitter @DrIagoPinal

  • IP-F, JCM, KP and SM-B contributed equally.

  • 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. Both Dr. ALM and IP-F act as guarantors of the study.

  • 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. This work was also supported by the Peter Buck and the Huayi and Siuling Zhang Discovery Fund.

  • 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.