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OBJECTIVE: To investigate the variability in the expression profile of genes associated with polymyositis (PM), explore the potential molecular mechanisms underlying PM, and predict novel targets for intervention. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Rheumatology, Taizhou Municipal Hospital, Taizhou, China, from August to November 2023. METHODOLOGY: Three microarray datasets (GSE3112, GSE39454, and GSE128470) were extracted from the gene expression omnibus (GEO). The analysis of this research involved identifying the differentially expressed genes (DEGs) in PM compared to normal samples. Enrichment analysis, gene-microRNA, gene-transcription factor (TF), and protein-protein interaction (PPI) network studies were conducted to identify hub genes and relevant pathways. Additionally, the drug-gene interaction database (DGIdb) was used to predict therapeutic medications. RESULTS: Eighty-eight DEGs were identified. The enrichment analysis results highlighted the significant involvement of downregulated DEGs in antigen processing and presentation. Based on the PPI networks, seven hub genes with high connectivity degrees were selected including a cluster of differentiation 74 (CD74), human leukocyte antigen (HLA)-DPA1, HLA-B, guanylate-binding protein 1 (GBP1), recombinant 2', 5'-oligoadenylate synthetase 1 (OAS1), HLA-C, and HLA-E. CONCLUSION: This research screened-out core genes, projected prospective therapeutic medications, discovered DEGs between PM and normal samples, and offered fresh perspectives for additional research into the possible mechanism and therapeutic targets of PM. KEY WORDS: Polymyositis, DEGs, Hub genes, Bioinformatics, Potential therapeutic agents.
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Perfilación de la Expresión Génica , Polimiositis , Mapas de Interacción de Proteínas , Humanos , Polimiositis/genética , Polimiositis/tratamiento farmacológico , Redes Reguladoras de Genes , Biología Computacional , MicroARNs/genética , Bases de Datos Genéticas , TranscriptomaRESUMEN
Background: Polymyositis (PM) is an acquirable muscle disease with proximal muscle involvement of the extremities as the main manifestation; it is a category of idiopathic inflammatory myopathy. This study aimed to identify the key biomarkers of PM, while elucidating PM-associated immune cell infiltration and immune-related pathways. Methods: The gene microarray data related to PM were downloaded from the Gene Expression Omnibus database. The analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were performed on differentially expressed genes (DEGs). The hub genes of PM were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm, and the diagnostic accuracy of hub markers for PM was assessed using the receiver operating characteristic curve. In addition, the level of infiltration of 28 immune cells in PM and their interrelationship with hub genes were analyzed using single-sample GSEA. Results: A total of 420 DEGs were identified. The biological functions and signaling pathways closely associated with PM were inflammatory and immune processes. A series of four expression modules were obtained by WGCNA analysis, with the turquoise module having the highest correlation with PM; 196 crossover genes were obtained by combining DEGs. Subsequently, six hub genes were finally identified as the potential biomarkers of PM using LASSO algorithm and validation set verification analysis. In the immune cell infiltration analysis, the infiltration of T lymphocytes and subpopulations, dendritic cells, macrophages, and natural killer cells was more significant in the PM. Conclusion: We identified the hub genes closely related to PM using WGCNA combined with LASSO algorithm, which helped clarify the molecular mechanism of PM development and might have great significance for finding new immunotherapeutic targets, and disease prevention and treatment.
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Biología Computacional , Polimiositis , Biomarcadores/metabolismo , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Polimiositis/genéticaRESUMEN
OBJECTIVE: This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM). METHODS: Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1ß) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM. RESULTS: The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1ß in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1ß as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1ß rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1ß blockade using neutralizing IL-1ß monoclonal antibody or siRNA of IL-1ß suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1ß and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum. CONCLUSION: NLRP3/caspase-1/IL-1ß axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.
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Inflamasomas , Polimiositis , Adenosina Trifosfato , Animales , Caspasa 1/genética , Caspasa 1/metabolismo , Inflamasomas/metabolismo , Lipopolisacáridos , Complejo Mayor de Histocompatibilidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Polimiositis/genética , ARN Interferente Pequeño , Ratas , Regulación hacia ArribaRESUMEN
OBJECTIVE: Polymyositis (PM) and dermatomyositis (DM) are heterogeneous disorders. However, the etiology of PM/DM development has not been thoroughly clarified. METHODS: Gene expression data of PM/DM were obtained from Gene Expression Omnibus. We used robust rank aggregation (RRA) to identify differentially expressed genes (DEGs). Gene Ontology functional enrichment and pathway analyses were used to investigate potential functions of the DEGs. Weighted gene co-expression network analysis (WGCNA) was used to establish a gene co-expression network. CIBERSORT was utilized to analyze the pattern of immune cell infiltration in PM/DM. Protein-protein interaction (PPI) network, Venn, and association analyses between core genes and muscle injury were performed to identify hub genes. Receiver operating characteristic analyses were executed to investigate the value of hub genes in the diagnosis of PM/DM, and the results were verified using the microarray dataset GSE48280. RESULTS: Five datasets were included. The RRA integrated analysis identified 82 significant DEGs. Functional enrichment analysis revealed that immune function and the interferon signaling pathway were enriched in PM/DM. WGCNA outcomes identified MEblue and MEturquoise as key target modules in PM/DM. Immune cell infiltration analysis revealed greater macrophage infiltration and lower regulatory T-cell infiltration in PM/DM patients than in healthy controls. PPI network, Venn, and association analyses of muscle injury identified five putative hub genes: TRIM22, IFI6, IFITM1, IFI35, and IRF9. CONCLUSIONS: Our bioinformatics analysis identified new genetic biomarkers of the pathogenesis of PM/DM. We demonstrated that immune cell infiltration plays a pivotal part in the occurrence of PM/DM.
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Dermatomiositis , Polimiositis , Biomarcadores , Biología Computacional , Dermatomiositis/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Polimiositis/genéticaRESUMEN
Oxidative damage-induced mitochondrial dysfunction may activate muscle catabolism and autophagy pathways to initiate muscle weakening in idiopathic inflammatory myopathies (IIMs). In this study, Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number were assessed and their association with the risk of polymyositis and dermatomyositis (PM/DM) was evaluated. Excessive D-loop SNPs (8.779 ± 1.912 vs. 7.972 ± 1.903, p = 0.004) correlated positively with mtDNA copy number (0.602 ± 0.457 vs. 0.300 ± 0.118, p < 0.001). Compared with that of the controls, the mtDNA of PM/DM patients showed D-loop SNP accumulation. In addition, the distribution frequencies of 16304C (p = 0.047) and 16519C (p = 0.043) were significantly higher in the patients with PM/DM. Subsequent analysis showed that reactive oxygen species (ROS) generation was increased in PM/DM patients compared with that in the controls (18,477.756 ± 13,574.916 vs. 14,484.191 ± 5703.097, p = 0.012). Further analysis showed that the PM/DM risk-related allele 16304C was significantly associated with lower IL-4 levels (p = 0.021), while 16519C had a trend to be associated with higher IL-2 expression (p = 0.064). The allele 16519C was associated with a positive antinuclear antibody (ANA) status in PM/DM patients (p = 0.011). Our findings suggest that mitochondrial D-loop SNPs could be potential biomarkers for PM/DM risk and these SNPs associated with cytokine expression may be involved in the development of PM/DM. Further, mtDNA copy number-mediated mitochondrial dysfunction may precede the onset of PM/DM.
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Dermatomiositis , Polimiositis , Variaciones en el Número de Copia de ADN , ADN Mitocondrial/genética , Dermatomiositis/complicaciones , Dermatomiositis/genética , Humanos , Mitocondrias/genética , Polimorfismo de Nucleótido Simple , Polimiositis/complicaciones , Polimiositis/genéticaRESUMEN
A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene (GYS1), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.
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Enfermedad del Almacenamiento de Glucógeno , Enfermedades Musculares , Polimiositis , Adulto , Femenino , Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/patología , Humanos , Errores Innatos del Metabolismo Lipídico , Lípidos , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Distrofias Musculares , Mutación , Polimiositis/diagnóstico , Polimiositis/genéticaRESUMEN
Muscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.
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Proteína HMGB1/antagonistas & inhibidores , Imidazoles/farmacología , Indoles/farmacología , Fibras Musculares Esqueléticas/efectos de los fármacos , Miositis/prevención & control , Necroptosis/efectos de los fármacos , Polimiositis/genética , Animales , Anticuerpos Neutralizantes/farmacología , Proteína C-Reactiva/administración & dosificación , Proteína Ligando Fas/genética , Proteína Ligando Fas/inmunología , Femenino , Regulación de la Expresión Génica , Granzimas/genética , Granzimas/inmunología , Proteína HMGB1/genética , Proteína HMGB1/inmunología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibras Musculares Esqueléticas/inmunología , Fibras Musculares Esqueléticas/patología , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/inmunología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Miositis/inducido químicamente , Miositis/genética , Miositis/inmunología , Necroptosis/genética , Necroptosis/inmunología , Perforina/genética , Perforina/inmunología , Polimiositis/inmunología , Polimiositis/patología , Transducción de Señal , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patologíaRESUMEN
OBJECTIVE: Polymyositis (PM) is a chronic autoimmune connective tissue disease whose pathogenic mechanisms are unclear. This study aimed to identify the main genes and functionally enriched pathways involved in PM using weighted gene coexpression network analysis (WGCNA). METHODS: To identify the candidate genes of PM, microarray datasets GSE128470, GSE3112, GSE39454 and GSE125977 were obtained from the Gene Expression Omnibus database. The gene network of GSE128470 was constructed, and WGCNA was used to divide genes into different modules. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were applied to the most PM-related modules. The datasets were used to verify the expression profile and diagnostic capabilities of the hub genes. Additionally, gene set enrichment analysis (GSEA) was carried out. Moreover, gene signatures were then used as a search query to explore the connectivity map (CMap). RESULTS: A weighted gene coexpression network was constructed, and the genes were divided into 66 modules. The enriched functions and candidate pathway modules included interferon-γ, type I interferon, cellular response to interferon-γ, neutrophil activation, neutrophil degranulation, neutrophil-mediated immunity and neutrophil activation involved in the immune response. A total of 22 hub genes were identified. The Mann-Whitney U test was performed on these 22 genes using the three datasets of muscle samples and one dataset of whole blood samples, and two genes significantly differentially expressed in all datasets were obtained: VCAM1 and LY96. Receiver operating characteristic curve analysis determined that VCAM1 and LY96 gene expression can distinguish PM from healthy controls (the area under the curve [AUC] was greater than 0.75). Logistic regression analysis was performed on the combination of LY96 and VCAM1. The accuracy, sensitivity, specificity, and AUC of the combination reached 1.0. GSEA of VCAM1 and LY96 revealed their relation to 'inflammatory response', 'TNF-α signalling via NF-κB', 'complement' and 'myogenesis'. CMap research revealed a few compounds with the potential to counteract the effects of the dysregulated molecular signature in PM. CONCLUSIONS: We used WGCNA to observe all aspects of PM, which helped to elucidate the molecular mechanisms of PM onset and progression and provide candidate targets for the diagnosis and treatment of PM. Key Points ⢠Four microarray datasets were analysed in patients with polymyositis and healthy controls, and VCAM1 and LY96 were significant genes in all datasets. ⢠GSEA of VCAM1 and LY96 revealed that they were mainly related to 'inflammatory response', 'TNF-α signalling via NF-κB', 'complement' and 'myogenesis'. ⢠CMap found a few compounds such as dimethyloxalylglycine and HNMPA-(AM)3 with the potential to counteract the effects of the dysregulated molecular signature in PM.
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Perfilación de la Expresión Génica , Polimiositis , Biomarcadores/metabolismo , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Interferón gamma , FN-kappa B , Polimiositis/tratamiento farmacológico , Polimiositis/genética , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Macrophage migration and infiltration contribute to the pathogenesis of polymyositis (PM). This study aims to investigate the effect and underlying mechanism of miR-409-3p on macrophage migration in PM. METHODS: The GSE143845 database was used to predict the altered expression of microRNAs (miRNAs) in PM. The quantitative real-time PCR (qRT-PCR), western blot and Transwell assay were performed to detect migration of macrophages and expressions of related molecules. A luciferase activity assay was conducted to confirm the binding of miR-409-3p and CXCR4 3'-UTR. Next, a mouse model of experimental autoimmune myositis (EAM) was established. Haematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were used to measure associated factors. RESULTS: MiR-409-3p was downregulated in PM of GSE143845 database and patients. Differently, the serum creatine kinase (s-CK), TNF-α, and IL-6 in patients with PM were increased. Furthermore, miR-409-3p mimic transfection reduced the migration of macrophages and CXCR4 levels, while miR-409-3p inhibitor exerted the opposite effects. CXCR4 was a target of miR-409-3p, and the effect of CXCR4 on promoting macrophage migration was reversed by miR-409-3p mimic. In vivo, miR-409-3p agomir injection reduced inflammatory cells, macrophages, and TNFα and IL-6 levels in muscles and serum of EAM mouse models. CONCLUSIONS: In conclusion, miR-409-3p reduces the migration of macrophages through negatively regulating CXCR4 expression in PM.
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MicroARNs , Polimiositis , Receptores CXCR4/genética , Animales , Movimiento Celular/genética , Proliferación Celular , Humanos , Macrófagos/metabolismo , Ratones , MicroARNs/metabolismo , Polimiositis/genética , Polimiositis/metabolismo , Transducción de SeñalAsunto(s)
Ciclosporina/administración & dosificación , Etopósido/administración & dosificación , Síndrome de Activación Macrofágica , Proteínas de la Membrana/genética , Metilprednisolona/administración & dosificación , Polimiositis , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adolescente , Antirreumáticos/administración & dosificación , Autoanticuerpos/sangre , Examen de la Médula Ósea/métodos , Homocigoto , Humanos , Síndrome de Activación Macrofágica/sangre , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Síndrome de Activación Macrofágica/terapia , Masculino , Mutación Missense , Planificación de Atención al Paciente , Polimiositis/sangre , Polimiositis/tratamiento farmacológico , Polimiositis/genética , Polimiositis/fisiopatología , Inducción de Remisión/métodos , Inhibidores de Topoisomerasa II/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVES: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. METHODS: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. RESULTS: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. CONCLUSIONS: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.
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Enfermedades Autoinmunes/genética , Enfermedades Musculares/genética , Miositis por Cuerpos de Inclusión/genética , Miositis/genética , Adulto , Animales , Apolipoproteínas A/metabolismo , Biopsia , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Moléculas de Adhesión Celular/metabolismo , Técnicas de Cultivo de Célula , Dermatomiositis/genética , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Femenino , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Interleucina-8/metabolismo , Aprendizaje Automático , Masculino , Ratones , Mucoproteínas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miositis/patología , Polimiositis/genética , TranscriptomaRESUMEN
Polymyositis (PM) and dermatomyositis (DM) are both classified as idiopathic inflammatory myopathies. They share a few common characteristics such as inflammation and muscle weakness. Previous studies have indicated that these diseases present aspects of an auto-immune disorder; however, their exact pathogenesis is still unclear. In this study, three gene expression datasets (PM: 7, DM: 50, Control: 13) available in public databases were used to conduct meta-analysis. We then conducted expression quantitative trait loci analysis to detect the variant sites that may contribute to the pathogenesis of PM and DM. Six-hundred differentially expressed genes were identified in the meta-analysis (false discovery rate (FDR) < 0.01), among which 317 genes were up-regulated and 283 were down-regulated in the disease group compared with those in the healthy control group. The up-regulated genes were significantly enriched in interferon-signaling pathways in protein secretion, and/or in unfolded-protein response. We detected 10 single nucleotide polymorphisms (SNPs) which could potentially play key roles in driving the PM and DM. Along with previously reported genes, we identified 4 novel genes and 10 SNP-variant regions which could be used as candidates for potential drug targets or biomarkers for PM and DM.
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Dermatomiositis/genética , Polimiositis/genética , Biomarcadores , Estudios de Casos y Controles , Bases de Datos Genéticas , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Interferones/genética , Miositis/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Respuesta de Proteína Desplegada/genéticaRESUMEN
BACKGROUND: Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed. OBJECTIVE: A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause. METHODS: Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed. RESULTS: Whole genome resequencing identified a pathological variant in the SLC25A12 gene, resulting in a leucine to proline substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress. CONCLUSIONS: This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy.
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Sistemas de Transporte de Aminoácidos Acídicos/genética , Antiportadores/genética , Ácido Aspártico/genética , Enfermedades de los Perros/genética , Ácido Glutámico/genética , Mitocondrias/genética , Mutación/genética , Polimiositis/veterinaria , Animales , Ácido Aspártico/metabolismo , Dermatomiositis/metabolismo , Enfermedades de los Perros/metabolismo , Perros , Ácido Glutámico/metabolismo , Humanos , Mitocondrias/metabolismo , Miositis/genética , Oxidación-Reducción , Polimiositis/genética , Polimiositis/metabolismoRESUMEN
Polymyositis with mitochondrial pathology (PM-Mito) is a rare form of idiopathic inflammatory myopathy with no definite diagnostic criteria and similarities to both PM and sporadic inclusion body myositis (s-IBM). The aim of this study is to address the dilemma of whether PM-Mito is a subtype of inflammatory myopathy or represents a disease falling into the spectrum of s-IBM. Herein, we report four female patients diagnosed with PM-Mito, highlighting their rather atypical clinical and histopathological characteristics that seem to indicate a diagnosis away from s-IBM. Muscle weakness was rather proximal and symmetrical and lacked the selective pattern observed in s-IBM. Patients had large-scale deletions in mtDNA, reflecting the mitochondrial component in the pathology of the disease. Conclusively, our study adds to the limited data in the literature on whether PM-Mito is a distinct form of myositis or represents a prodromal stage of s-IBM. Although the latter seems to be supported by a substantial body of evidence, there are, however, important differences, such as the different patterns of muscle weakness, and the good response to treatment observed in some patients. Larger-scale studies are certainly needed to clarify pathogenesis and clinical characteristics of PM-Mito patients, especially in therapeutic and prognostic terms.
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Mitocondrias Musculares/patología , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/patología , Polimiositis/patología , Adulto , Anciano , Biopsia , ADN Mitocondrial/genética , Diagnóstico Diferencial , Femenino , Eliminación de Gen , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/genética , Debilidad Muscular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/fisiopatología , Polimiositis/tratamiento farmacológico , Polimiositis/genética , Polimiositis/fisiopatología , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
AIM: Dermatomyositis (DM) and polymyositis (PM) are refractory systemic autoimmune diseases with unknown pathogenesis. miRNAs is an important epigenetic mechanism to regulate gene expression. METHODS: We performed whole miRNAs analysis, transcription analysis and the association between miRNAome and mRNAome. RESULTS: For transcription and miRNAs analysis, there were common and specific mRNAs and miRNAs in the muscles of DM and PM. Among them, the expression levels of miR-196a-5p and CPM were negatively correlated in PM, miR-193b-3p and NECAP2 were negatively correlated in DM and PM. Protein carboxypeptidase M (CPM) plays roles in the degradation of extracellular proteins and in the migration and invasion of cancer cells, and protein NECAP2 plays roles in adaptor protein AP-1-mediated fast recycling from early endosomes. The functions of them in the pathogenesis of DM/PM need further studies. CONCLUSION: Our study identified and confirmed differentially miRNAs and mRNAs in DM and PM. Our observations have laid the groundwork for further diagnostic and mechanistic studies of DM and PM.
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Dermatomiositis/genética , Perfilación de la Expresión Génica , MicroARNs/genética , Polimiositis/genética , ARN Mensajero/genética , Transcriptoma , Biomarcadores , Biopsia , Estudios de Casos y Controles , Biología Computacional/métodos , Dermatomiositis/metabolismo , Dermatomiositis/patología , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Humanos , Mioblastos/metabolismo , Polimiositis/metabolismo , Polimiositis/patología , Interferencia de ARN , Reproducibilidad de los ResultadosRESUMEN
The aim of our study was to investigate the association between single nucleotide polymorphisms (SNPs) in the BANK1 gene and polymyositis/dermatomyositis (PM/DM) in a Chinese Han population. In total, 363 PM patients, 654 DM patients, and 1280 healthy controls were recruited and genotyped using the Sequenom MassArray system. A significant allele association was observed in rs3733197 among the PM/DM patients (OR 0.81, 95%CI 0.70-0.94, Pc = 1.83 × 10-2). Notably, rs3733197 was associated with DM and PM/DM patients with ILD involvement (Pc = 0.026; Pc = 6.0 × 10-3, respectively). However, no statistically significant difference was observed in the allele or genotype frequencies of three SNPs (rs4522865, rs17266594, and rs10516487) among the DM, PM, and PM/DM patients and healthy controls (all Pc > 0.05). This study was the first to demonstrate that a BANK1 gene SNP (rs3733197) could confer genetic predisposition in PM/DM patients and PM/DM patients with ILD in a Chinese Han population.
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Proteínas Adaptadoras Transductoras de Señales/genética , Dermatomiositis/genética , Proteínas de la Membrana/genética , Polimiositis/genética , Adulto , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
This study aims to explore the roles of cysteine-rich protein 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/CCN2) and vascular endothelial growth factor (VEGF) in the vascular process of polymyositis (PM)/dermatomyositis (DM).Real-time quantitative polymerase chain reaction was used to determine the mRNA expression of Cyr61, CTGF, and VEGF in muscle tissues of initially treated PM/DM patients and controls. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of Cyr61, CTGF, and VEGF of initially treated PM/DM patients before and after treatment. Data were statistically analyzed using statistical software SPSS 17.0.The mRNA expression levels of Cyr61, CTGF, and VEGF in muscle tissues were higher in the PM and DM groups than in the control group (Pâ<â.05). Differences in the mRNA expression levels of Cyr61, CTGF, and VEGF in muscle tissues between the PM and DM groups were not statistically significant (Pâ>â.05). Before treatment, the serum levels of Cyr61, CTGF, and VEGF were higher in the PM and DM groups than in the control group (Pâ<â.05). Furthermore, in the PM and DM groups, the expression levels of Cyr61, CTGF, and VEGF in serum at 6 months after treatment were lower than those before treatment (Pâ<â.05).Cyr61, CTGF, and VEGF are involved in the pathogenesis of PM/DM. These may be involved in the pathogenesis mainly by affecting the formation of blood vessels and promoting inflammatory response. This suggests that microvascular lesions play an important role in the immune pathogenesis of inflammatory myopathy PM/DM.
Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/genética , Proteína 61 Rica en Cisteína/genética , Dermatomiositis/genética , Polimiositis/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Factor de Crecimiento del Tejido Conjuntivo/sangre , Proteína 61 Rica en Cisteína/sangre , Dermatomiositis/sangre , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimiositis/tratamiento farmacológico , Polimiositis/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies, a chronic inflammatory disorder clinically characterized by muscle weakness and inflammatory cell infiltrates in muscle tissue. In PM, a major component of inflammatory cell infiltrates is CD8+ T cells, whereas in DM, CD4+ T cells, plasmacytoid dendritic cells, and B cells predominate. In this study, with the aim to differentiate involvement of CD4+ and CD8+ T-cell subpopulations in myositis subgroups, we investigated transcriptomic profiles of T cells from peripheral blood of patients with myositis. METHODS: Total RNA was extracted from CD4+ T cells (PM = 8 and DM = 7) and CD8+ T cells (PM = 4 and DM = 5) that were isolated from peripheral blood mononuclear cells via positive selection using microbeads. Sequencing libraries were generated using the Illumina TruSeq Stranded Total RNA Kit and sequenced on an Illumina HiSeq 2500 platform, yielding about 50 million paired-end reads per sample. Differential gene expression analyses were conducted using DESeq2. RESULTS: In CD4+ T cells, only two genes, ANKRD55 and S100B, were expressed significantly higher in patients with PM than in patients with DM (false discovery rate [FDR] < 0.05, model adjusted for age, sex, HLA-DRB1*03 status, and RNA integrity number [RIN]). On the contrary, in CD8+ T cells, 176 genes were differentially expressed in patients with PM compared with patients with DM. Of these, 44 genes were expressed significantly higher in CD8+ T cells from patients with PM, and 132 genes were expressed significantly higher in CD8+ T cells from patients with DM (FDR < 0.05, model adjusted for age, sex, and RIN). Gene Ontology analysis showed that genes differentially expressed in CD8+ T cells are involved in lymphocyte migration and regulation of T-cell differentiation. CONCLUSIONS: Our data strongly suggest that CD8+ T cells represent a major divergence between PM and DM patients compared with CD4+ T cells. These alterations in the gene expression in T cells from PM and DM patients might advocate for distinct immune mechanisms in these subphenotypes of myositis.
Asunto(s)
Dermatomiositis/genética , Perfilación de la Expresión Génica/métodos , Polimiositis/genética , Linfocitos T/metabolismo , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Dermatomiositis/sangre , Dermatomiositis/diagnóstico , Diagnóstico Diferencial , Femenino , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Polimiositis/sangre , Polimiositis/diagnósticoRESUMEN
The downregulation of microRNA (miR)-381 has been detected in various diseases. The present study aimed to investigate the effects, and underlying mechanisms of miR-381 on inflammation and macrophage infiltration in polymyositis (PM). A mouse model of experimental autoimmune myositis (EAM) was generated in this study. Hematoxylin and eosin staining was conducted to detect the inflammation of muscle tissues. In addition, ELISA and immunohistochemistry were performed to determine the expression levels of associated factors, and reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression levels of related mRNAs and proteins. A luciferase activity assay was used to confirm the binding of miR-381 and high mobility group box 1 (HMGB1) 3' untranslated region. Transwell assays were also performed to assess the migratory ability of macrophages. The results demonstrated that serum creatine kinase (s-CK), HMGB1 and cluster of differentiation (CD)163 expression in patients with PM were increased compared within healthy controls. Conversely, the expression levels of miR-381 were downregulated in patients with PM. Furthermore, high HMGB1 expression was associated with poor survival rate in patients with PM. In the mouse studies, muscle inflammation and CD163 expression were decreased in the anti-IL-17 and anti-HMGB1 groups, compared with in the EAM model group. The expression levels of s-CK, HMGB1, IL-17 and intercellular adhesion molecule (ICAM)-1 were also downregulated in response to anti-IL-17 and anti-HMGB1. These findings indicated that HMGB1 was closely associated with inflammatory responses. In addition, the present study indicated that transfection of macrophages with miR-381 mimics reduced the migration of inflammatory macrophages, and the expression levels of HMGB1, IL-17 and ICAM-1. Conversely, miR-381 inhibition exerted the opposite effects. The effects of miR-381 inhibitors were reversed by HMGB1 small interfering RNA. In conclusion, miR-381 may reduce inflammation and the infiltration of macrophages; these effects were closely associated with the downregulation of HMGB1.
Asunto(s)
Proteína HMGB1/genética , Macrófagos/inmunología , MicroARNs/metabolismo , Enfermedad Autoinmune Experimental del Sistema Nervioso/genética , Polimiositis/genética , Adulto , Anciano , Animales , Antígenos CD/sangre , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/sangre , Antígenos de Diferenciación Mielomonocítica/inmunología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Estudios de Casos y Controles , Movimiento Celular/genética , Creatina Quinasa/sangre , Regulación hacia Abajo , Femenino , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/sangre , Proteína HMGB1/inmunología , Proteína HMGB1/metabolismo , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Persona de Mediana Edad , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Enfermedad Autoinmune Experimental del Sistema Nervioso/sangre , Enfermedad Autoinmune Experimental del Sistema Nervioso/inmunología , Enfermedad Autoinmune Experimental del Sistema Nervioso/patología , Toxina del Pertussis/inmunología , Polimiositis/sangre , Polimiositis/inmunología , Polimiositis/mortalidad , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores de Superficie Celular/sangre , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo , Tasa de Supervivencia , Regulación hacia ArribaRESUMEN
BACKGROUND: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM. METHODS: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human leucocyte antigen (HLA) associated with DM autoantibodies and DM or PM single-nucleotide polymorphisms (suggestive significance in the Immunochip project, P < 2.25 × 10- 5) in healthy control subjects with latitude. All variables were analysed against latitude using ordered logistic regression, adjusted for sex. RESULTS: The prevalence of DM, as a proportion of DM and PM combined, and the presence of anti-transcription intermediary factor 1 (anti-TIF1-γ) autoantibodies were both significantly negatively associated with latitude (OR 0.96, 95% CI 0.95-0.98, P < 0.001; and OR 0.95, 95% CI 0.92-0.99, P = 0.004, respectively). HLA alleles significantly associated with anti-Mi-2 and anti-TIF1-γ autoantibodies also were strongly negatively associated with latitude (OR 0.97, 95% CI 0.96-0.98, P < 0.001 and OR 0.98, 95% CI 0.97-0.99, P < 0.001, respectively). The frequency of five PM- or DM-associated SNPs showed a significant association with latitude (P < 0.05), and the direction of four of these associations was consistent with the latitude associations of the clinical phenotypes. CONCLUSIONS: These results lend some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM.