Project description:Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy (IIM). Significant molecular similarities have been recently detected between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to full-blown IBM, and prompting the inclusion of PM-Mito as an early form of IBM (eIBM) within the IBM spectrum. Both early and late stages of IBM show mitochondrial abnormalities, suggesting mitochondrial dysfunction is an early feature of IBM. The primary objective of this study was to characterize the mitochondrial phenotype in eIBM/PM-Mito at histological, ultrastructural, and molecular levels and to study the possible interplay between mitochondrial dysfunction and inflammation. Skeletal muscle biopsies of 27 patients with eIBM/PM-Mito and 27 full-blown IBM were included for morphological and ultrastructural analysis. Mitochondrial DNA (mtDNA) copy number and deletions were assessed by qPCR and long-range PCR, respectively. In addition, full-length single-molecule sequencing of the mtDNA enabled precise mapping of deletions. Protein and RNA levels were studied using unbiased proteomic profiling, immunoblotting, and bulk RNA sequencing. Cell-free mtDNA (cfmtDNA) was measured in the serum of full-blown IBM patients.
Project description:Inclusion body myositis (IBM) is an autoimmune and degenerative disorder of skeletal muscle. The B cell infiltrates in IBM muscle tissue are predominantly fully differentiated antibody-secreting plasma cells, with scarce naïve or memory B cells. The role of this infiltrate in the disease pathology is not well understood. To better define the humoral response in IBM, we used adaptive immune receptor repertoire sequencing to generate large B cell receptor (BCR) repertoire libraries from IBM muscle biopsies and compared them to those generated from dermatomyositis (DM), polymyositis (PM), and circulating CD27+ memory B cells, derived from healthy controls and antibody secreting cells (ASC) collected following vaccination. The repertoire properties of the IBM infiltrate included: expanded clones that equaled or exceeded the highly clonal vaccine-associated ASC repertoire; reduced somatic mutation selection pressure in the complementary determining regions and framework regions; and enriched usage of class switched IgG and IgA isotypes, with a minor population of IgM expressing cells. These IBM IgM-expressing population revealed unique features, including an elevated somatic mutation frequency and distinct CDR3 physicochemical properties., These findings demonstrate that the IBM muscle BCR repertoire is highly distinct from DM and PM and circulating antigen-experienced subsets, suggesting that it may form through selection by a disease-specific set of antigens.
Project description:We investigated the gene and exon espression profiling in muscle biopsies of patients affected by inclusion body myosistis, polymyositis and in normal muscle controls
Project description:Myositis is characterised by muscle inflammation and weakness. Although generally thought to be driven by a systemic autoimmune response, increasing evidence suggests that intrinsic changes in the muscle might also contribute to the pathogenesis. Long non-coding RNAs (lncRNAs) are a family of novel genes that regulate gene transcription and translation. To determine the potential role of lncRNAs, we employed next generation sequencing to examine the transcriptome in muscle biopsies obtained from two histologically distinct patient populations, inclusion body myositis (IBM) and anti-Jo-1-associated myositis (Jo-1).
Project description:Idiopathic inflammatory myopathies (IIMs) encompass a diverse group of autoimmune disorders affecting skeletal muscle, including dermatomyositis (DM), anti-synthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Polymyositis with mitochondrial pathology (PM-Mito) has been proposed as a potential IIM subtype, with emerging evidence suggesting it may represent an early form of IBM. IBM is characterized by unique clinical features, such as insidious onset and resistance to immunotherapies, alongside hallmark histopathological findings, including rimmed vacuoles, cytoplasmic protein aggregates, CD8+ T cell-dominated inflammation, and prominent mitochondrial abnormalities. Mitochondrial dysfunction, ragged-red fibers, and disrupted oxidative phosphorylation are increasingly recognized as central contributors to IBM pathology, implicating mitochondrial processes in both muscle weakness and chronic inflammation.
This study presents a longitudinal and cross-sectional proteomic analysis of IBM in comparison to other IIM subtypes. We identified both established and novel hallmarks of IBM, particularly highlighting mitochondrial dysfunction and immune dysregulation, while also examining PM-Mito as a potential precursor state to IBM. Using an unbiased mass spectrometry-based proteomic approach, we identified a distinct proteomic signature for IBM characterized by mitochondrial alterations and type II interferon-associated immune pathway dysregulation. PM-Mito samples displayed a dysregulation of immune regulatory proteins and mitochondrial pathways. This study reinforces the unique molecular profile of IBM compared to other IIM subtypes while strengthening the concept of a disease continuum between IBM and PM-Mito. By uncovering shared mitochondrial and immune dysregulation in IBM and PM-Mito, these findings support the notion that PM-Mito may represent an early or transitional stage of IBM, providing new insights into disease progression and potential therapeutic targets.
