Muscle Disease Unit

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

During the last year, we completed numerous clinical projects involving myositis patients. A selection of published findings included the following: 1. We conducted a large RNA-sequencing study of 669 muscle biopsies identified distinct cytokine, cytokine receptor, and immune checkpoint expression patterns across different forms of myositis. Inclusion body myositis (IBM) showed the strongest type 1 inflammatory signature, with IBM-specific upregulation of the CCL5–CCR5 and XCL1–XCR1 axes. Dermatomyositis (DM), anti-Jo1, and anti-PM/Scl subgroups also exhibited type 1 inflammation but with different gene profiles, while immune-mediated necrotizing myopathy (IMNM) had few differentially expressed cytokines. These findings highlight subgroup-specific inflammatory pathways and suggest new therapeutic targets, particularly for IBM. 2. Along with collaborators, we completed a study demonstrated for the first time that patients with anti-HMGCR immune-mediated necrotizing myopathy (IMNM) harbor HMGCR-reactive CD4+ T cells in both blood and muscle. Using natural antigen processing assays, we identified seven core HMGCR peptides that consistently elicited robust T-cell responses across patients, independent of HLA subtype. T-cell receptor sequencing revealed shared antigen-reactive motifs enriched in patient muscle, indicating a focused, disease-specific immune response. These findings implicate CD4+ T cells as active drivers of pathogenesis and provide a foundation for developing antigen-specific monitoring and therapies. 3. We performed work which overturned the longstanding belief that myositis autoantibodies cannot enter living muscle cells. Using confocal microscopy and RNA-sequencing, we showed that autoantibodies accumulate within myofibers at the site of their target antigens and induce gene expression changes consistent with disrupted protein function. For example, anti-Mi2 antibodies caused derepression of Mi2/NuRD-regulated genes, while anti-PM/Scl antibodies led to accumulation of RNAs normally degraded by the nuclear exosome. These results demonstrate that autoantibody internalization contributes directly to disease mechanisms, supporting therapeutic strategies that reduce pathogenic antibody levels.