Spatial and cell type specific molecular genetic investigations of inflammatory myopathies with selective perifascicular injury [RNA]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE331197 | GEO | 2026/07/15
REPOSITORIES: GEO
Similar Datasets
Project description:Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic autoimmune disease often with multisystem involvement. Targeted therapy is still lacking. Efficient serum or histological markers to measure disease activity and predict disease course are missing. Perifascicular myofiber atrophy is a hall mark of dermatomyositis (DM). Despite decades of research, the mechanism of perifascicular atrophy is still incompletely understood. Across other IIM subtypes, perifascicular myofiber necrosis is also the hall mark pathology for antisynthetase syndrome associated myositis (ASyS)5, and can be seen in a subset of lupus myositis (LM). We hypothesize that direct comparison between tissue within the diseased perifascicular regions (PF) and the relatively normal centro-fascicular (CF) regions will help narrow down tissue specific drivers underlying the muscle injury (necrosis versus atrophy) in a disease specific manner.
2026-07-15 | GSE330891 | GEO
Project description:Objectives: The idiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune conditions of skeletal muscle inflammation and weakness. MicroRNAs (miRNAs) are short, non-coding RNA which regulate gene expression of target mRNAs. The aim of this study was to profile miRNA and mRNA in IIM and identify miRNA-mRNA relationships which may be relevant to disease. Materials and methods: mRNA and miRNA in whole blood samples from 7 polymyositis (PM), 7 dermatomyositis (DM), 5 inclusion body myositis (IBM) and 5 non-myositis controls was profiled using next generation RNA sequencing. Gene ontology and pathway analyses were performed using GOseq and Ingenuity Pathway Analysis. Dysregulation of miRNAs and opposite dysregulation of predicted target mRNAs in IIM subgroups was validated using RTqPCR and investigated by transfecting human skeletal muscle cells with miRNA mimic. Results Analysis of differentially expressed genes showed that interferon signalling and anti-viral response pathways were upregulated in PM and DM compared to controls. An anti-Jo1 autoantibody positive subset of PM and DM (n=5) had more significant upregulation and predicted activation of interferon signalling and highlighted T-helper (Th1 and Th2) cell pathways. In miRNA profiling miR-96-5p was significantly upregulated in PM, DM and the anti-Jo1positive subset. RTqPCR replicated miR-96-5p upregulation and predicted mRNA target (ADK, CD28 and SLC4A10) downregulation. Transfection of a human skeletal muscle cell line with miR-96-5p mimic resulted in significant downregulation of ADK. Conclusion: MiRNA and mRNA profiling identified dysregulation of interferon signalling, anti-viral response and T-helper cell pathways, and indicates a possible role for miR-96-5p regulation of ADK in pathogenesis of IIM.
2019-07-31 | GSE125977 | GEO
Project description:Objective: In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers. Methods: Expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses. Results: Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNγ expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood. Conclusions: Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition.
2014-06-04 | GSE58173 | GEO
Project description:MHC-I overexpression in muscle biopsies is a hallmark of inflammatory myopathies.However the mechanisms of MHC-I overexpression in each disease is not well understood. Microarray analysis from MHC-I-microdissected myofibers showed a differential expression signature in each inflammatory myopathy. Innate immunity and IFN-I pathways are upregulated vs healthy controls, specifically in dermatomyositis (DM). RNA from MHC-I-positive myofibers were obtained from muscle biopsies of 5 patients with dermatomyositis, 5 with polymyositis, 4 with inclusion body myositis and normal looking fibers from healthy controls.
2013-12-01 | E-GEOD-48280 | biostudies-arrayexpress
Project description:Objective: In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers. Methods: Expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses. Results: Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNM-NM-3 expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood. Conclusions: Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition. Investigation of constitutive and immunoproteasomal subunit expression in muscle tissue of patients with inflammatory and non-inflammatory myopathies These transcriptomes were used as reference signatures of different immune cell types in order to estimate the contribution of immune cell transcripts to the muscle transcriptomes investigated in the datasets GSE2044, GSE3112, GSE5370, GSE39454, GSE3307, GSE13205, GSE10685.
2014-06-04 | E-GEOD-58173 | biostudies-arrayexpress
Project description:The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle clearance. In skeletal muscle, both systems’ excessive activation induces severe muscle loss. Although altered proteasomal function has been observed in various myopathies, the specific role of proteasomal activity in skeletal muscle has not been determined by loss-of-function approaches. Here, we report that muscle-specific deletion of a crucial proteasomal gene, Rpt3, resulted in profound muscle atrophy and decrease in force. Rpt3 null muscles showed reduced proteasomal activity in early age, accumulation of basophilic structure, disorganization of sarcomere, and formation of vacuoles and concentric membranous structures in electronmicroscope. We also observed accumulation of ubiquitin, p62, LC3, TDP43, FUS and VCP proteins. Proteasomal activity is important to preserve muscle mass and to maintain myofiber integrity. Our results suggest that inhibition/alteration of proteasomal activity can contribute to myofiber degeneration and weakness in muscle disorders, such as inclusion body myositis, characterized by accumulation of abnormal inclusions. Tibialis anterior muscles from Rpt3 null and control mice. each 3 mice.
2014-09-30 | E-GEOD-34896 | biostudies-arrayexpress
Project description:Objectives: This study aimed to investigate the association between immunoglobulin G (IgG) N-glycosylation patterns and the clinical endotypes of patients with idiopathic inflammatory myopathies (IIM), potentially informing disease classification and therapeutic target identification. Methods: We recruited 168 IIM patients and 52 healthy controls, and performed IgG N-glycosylation profiling using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and employed GlycoQuant for intact glycopeptide analysis. Clinical data were extracted, and statistical analyses were conducted to correlate glycosylation profiles with clinical manifestations. Unsupervised clustering analysis was applied to identify novel IIM subgroups based on differential IgG N-glycosylation. Results: Our analysis revealed significant disparities in IgG N-glycosylation between IIM patients and controls, with 13 specific glycoforms exhibiting marked alterations. The level of fucosylated glycans was significantly higher in the IIM patients than healthy controls. Three distinct IIM endotypes were identified, each characterized by unique glycosylation signatures and clinical phenotypes. These endotypes were not congruent with conventional diagnostic subgroups and demonstrated associations with various clinical outcomes, including muscle weakness, interstitial lung disease (ILD), and serological profiles.
2024-12-03 | PXD058502 |
Project description:The precise mechanisms underlying the pathogenesis of idiopathic inflammatory myopathy (IIM) remain undefined. However, there has been increasing recognition that tissue-resident memory cells (TRMs) play an important role in the pathogenesis of systemic autoimmune disease. In IIM, TRM-associated transcriptional signatures have been reported, but on a very limited basis. By using multimodal single-cell RNA sequencing analysis in our established murine model of histidyl-tRNA synthetase (HRS)-induced myositis, we identified a prominent population of CD4+ TRMs in inflamed skeletal muscle. Muscle CD4+ TRMs exhibited high expression of genes encoding Cd69, Cxcr6, Runx3, and Prdm1, alongside low expression of Klf2, Ccr7, Sell, S1pr1, and Tcf7—a profile that is generally consistent with previous reports of TRM gene signature and that we validate through comparison to transcriptomic profiles of human muscle tissue. Detailed pathway analysis in our model indicates that muscle CD4+ TRMs contribute to innate immune regulatory pathways enriched for TNF and IFN-γ signaling. Furthermore, analysis of TCR clonotype distribution and CDR3 sequence similarity revealed pronounced clonal expansion of CD4⁺ TRMs relative to other T-cell subsets—a pattern that remained stable from 2 to 6 weeks post-immunization. Collectively, these results suggest a potential role for CD4+ TRMs in the pathogenesis of autoimmune myositis.
2026-07-17 | GSE335841 | GEO
Project description:The precise mechanisms underlying the pathogenesis of idiopathic inflammatory myopathy (IIM) remain undefined. However, there has been increasing recognition that tissue-resident memory cells (TRMs) play an important role in the pathogenesis of systemic autoimmune disease. In IIM, TRM-associated transcriptional signatures have been reported, but on a very limited basis. By using multimodal single-cell RNA sequencing analysis in our established murine model of histidyl-tRNA synthetase (HRS)-induced myositis, we identified a prominent population of CD4+ TRMs in inflamed skeletal muscle. Muscle CD4+ TRMs exhibited high expression of genes encoding Cd69, Cxcr6, Runx3, and Prdm1, alongside low expression of Klf2, Ccr7, Sell, S1pr1, and Tcf7—a profile that is generally consistent with previous reports of TRM gene signature and that we validate through comparison to transcriptomic profiles of human muscle tissue. Detailed pathway analysis in our model indicates that muscle CD4+ TRMs contribute to innate immune regulatory pathways enriched for TNF and IFN-γ signaling. Furthermore, analysis of TCR clonotype distribution and CDR3 sequence similarity revealed pronounced clonal expansion of CD4⁺ TRMs relative to other T-cell subsets—a pattern that remained stable from 2 to 6 weeks post-immunization. Collectively, these results suggest a potential role for CD4+ TRMs in the pathogenesis of autoimmune myositis.
2026-07-17 | GSE335819 | GEO
Project description:The precise mechanisms underlying the pathogenesis of idiopathic inflammatory myopathy (IIM) remain undefined. However, there has been increasing recognition that tissue-resident memory cells (TRMs) play an important role in the pathogenesis of systemic autoimmune disease. In IIM, TRM-associated transcriptional signatures have been reported, but on a very limited basis. By using multimodal single-cell RNA sequencing analysis in our established murine model of histidyl-tRNA synthetase (HRS)-induced myositis, we identified a prominent population of CD4+ TRMs in inflamed skeletal muscle. Muscle CD4+ TRMs exhibited high expression of genes encoding Cd69, Cxcr6, Runx3, and Prdm1, alongside low expression of Klf2, Ccr7, Sell, S1pr1, and Tcf7—a profile that is generally consistent with previous reports of TRM gene signature and that we validate through comparison to transcriptomic profiles of human muscle tissue. Detailed pathway analysis in our model indicates that muscle CD4+ TRMs contribute to innate immune regulatory pathways enriched for TNF and IFN-γ signaling. Furthermore, analysis of TCR clonotype distribution and CDR3 sequence similarity revealed pronounced clonal expansion of CD4⁺ TRMs relative to other T-cell subsets—a pattern that remained stable from 2 to 6 weeks post-immunization. Collectively, these results suggest a potential role for CD4+ TRMs in the pathogenesis of autoimmune myositis.
2026-07-17 | GSE336063 | GEO