2461: Transcriptional Derepression of CHD4/NuRD-regulated Genes in the Muscle of Patients with Dermatomyositis and anti-Mi2 Autoantibodies

Iago Pinal-Fernandez¹, Jose Cesar Milisenda², Katherine Pak¹, Sandra Muñoz-Braceras³, Maria Casal-Dominguez³, Jose Jiram Torres-Ruiz³, Stefania Dell´Orso⁴, Faiza Naz⁴, Gustavo Gutierrez-Cruz⁴, Yaiza Duque-Jaimez², Ana Matas-Garcia², Joan Padrosa⁵, Francesc J Garcia-Garcia², Mariona Guitart-Manpel², Gloria Garrabou², Ernesto Trallero-Araguas⁶, Brian Wallit⁷, Julie Paik⁸, Jemima Albayda⁸, Lisa Christopher-Stine⁸, Tom Lloyd⁹, Josep Maria Grau², Albert Selva-O’Callaghan⁶ and Andrew Mammen¹⁰, ¹National Institutes of Health, Bethesda, MD, ²Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain, ³Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁵CIBERER, Barcelona, Spain, Barcelona, Spain, ⁶Systemic Autoimmune Disease Unit, Vall d’Hebron Institute of Research, Barcelona, Spain, ⁷National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, ⁸Johns Hopkins University, Baltimore, MD, ⁹Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁰NIH, Bethesda, MD

Background/Purpose: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotizing 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 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 MADCAM, 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 titers, markers of disease activity, and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localized to the nucleus, MADCAM protein was present in the cytoplasm of perifascicular fibers, and SCRT1 protein was localized to myofiber nuclei.

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








I. Pinal-Fernandez: None; J. Milisenda: None; K. Pak: None; S. Muñoz-Braceras: None; M. Casal-Dominguez: None; J. Torres-Ruiz: None; S. Dell´Orso: None; F. Naz: None; G. Gutierrez-Cruz: None; Y. Duque-Jaimez: None; A. Matas-Garcia: None; J. Padrosa: None; F. Garcia-Garcia: None; M. Guitart-Manpel: None; G. Garrabou: None; E. Trallero-Araguas: None; B. Wallit: None; J. Paik: None; J. Albayda: Amgen, 5, Janssen, 5; L. Christopher-Stine: None; T. Lloyd: None; J. Grau: None; A. Selva-O’Callaghan: None; A. Mammen: None.