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          NIAMS Scientific Advances
          The Direct Binding of Anti-Mi2 Autoantibodies to Their Antigen Is Key to the Pathogenesis of Anti-Mi2 Dermatomyositis








NIAMS Advances


The Direct Binding of Anti-Mi2 Autoantibodies to Their Antigen Is Key to the Pathogenesis of Anti-Mi2 Dermatomyositis May 2, 2023
                                CLINICAL
        Andrew Mammen, M.D., Ph.D.
                                          |
              Muscle Disease Section
                                          |
              NIAMS IRP
        DescriptionThe clinical phenotype of dermatomyositis (DM) is uniquely influenced by the specific autoantibodies present. Compared to other patients, there is a greater risk of muscle weakness in patients with anti-Mi2 autoantibodies, which target a component of the nucleosome remodeling-deacetylase (NuRD) complex. According to the authors of the study, anti-Mi2 autoantibodies enter myofibers, inhibit chromodomain helicase DNA-binding protein 4 (CHD4), and subsequently alter the expression of a specific set of genes. The expression levels of these 135 genes identified in this study were linked to markers of disease severity and the titer of anti-Mi2 autoantibodies. Furthermore, the authors found that: (a) the anti-Mi2-specific gene set is enriched for genes regulated by the CHD4/NuRD complex, (b) immunoglobulin is present within the nuclei and cytoplasm of muscle fibers from anti-Mi2-positive DM patients, and (c) proteins encoded by the Mi2-specific genes are expressed within muscle fibers from anti-Mi2-positive patients.What is exciting about this article?Myositis refers to a variety of muscle conditions including DM. Anti-Mi2 DM is characterized by more prominent inflammation and myofiber necrosis than other types. According to this study, biopsies of patients with anti-Mi2-positive DM showed overexpression of more than 100 genes, including some not normally expressed in skeletal muscle. The study demonstrated for the first time that anti-Mi2 autoantibodies are not simply useful biomarkers for DM but also define distinct subtypes of DM with distinct gene expression patterns. This study confirmed that anti-Mi2 autoantibodies define a distinct subtype of dermatomyositis and suggested the possibility that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibers, inhibiting the CHD4/NuRD complex, and subsequently altering the expression of the genes defined in this study.How does this fit into the larger NIAMS portfolio?Dr. Mammen's research centers on the pathogenesis of autoimmune muscle diseases. The study revealed the pivotal role of anti-Mi2 autoantibody internalization in the pathogenesis of anti-Mi2 dermatomyositis. This breakthrough opens promising avenues for further investigation that may lead to the development of innovative treatments and, potentially, a cure for the disease.Grant supportAR041203
        Research Areas:
            Clinical Research
      Immunology
      Muscle Biology
                                        CORE Facilities:
            Genomic Technology Section
                    Reference:
            Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies.

    Pinal-Fernandez I, Milisenda JC, Pak K, Muñoz-Braceras S, Casal-Dominguez M, Torres-Ruiz J, Dell'Orso S, Naz F, Gutierrez-Cruz G, Duque-Jaimez Y, Matas-Garcia A, Padrosa J, Garcia-Garcia FJ, Guitart-Mampel M, Garrabou G, Trallero-Araguás E, Walitt B, Paik JJ, Albayda J, Christopher-Stine L, Lloyd TE, Grau-Junyent JM, Selva-O'Callaghan A, Mammen AL
        

                    Ann Rheum Dis.
        
                    2023 Aug;
        
                    82(8).
        
                    doi: 10.1136/ard-2023-223873
                            PMID: 37130727
        Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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