MicroRNA-10a Regulation of Proinflammatory Mediators: An Important Component of Untreated Juvenile Dermatomyositis
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE49062 | GEO | 2016/06/06
SECONDARY ACCESSION(S): PRJNA212793
REPOSITORIES: GEO
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Project description:Background :To evaluate the impact of the duration of chronic inflammation on gene expression in skeletal muscle biopsies (MBx) from untreated children with juvenile dermatomyositis (JDM) and identify genes and biological processes associated with the disease progression, expression profiling data from 16 girls with active symptoms of JDM greater or equal to 2 months were compared with 3 girls with active symptoms less than 2 months. Results: Seventy-nine genes were differentially expressed between the groups with long or short duration of untreated disease. Genes involved in immune responses and vasculature remodeling were expressed at a higher level in muscle biopsies from children with greater or equal to 2 months of symptoms, while genes involved in stress responses and protein turnover were expressed at a lower level. Among the 79 genes, expression of 9 genes showed a significant linear regression relationship with the duration of untreated disease. Five differentially expressed genes--HLA-DQA1, smooth muscle myosin heavy chain, clustering, plexin D1 and tenomodulin--were verified by quantitative RT-PCR. The chronic inflammation of longer disease duration was also associated with increased DC-LAMP+ and BDCA2+ mature dendritic cells, identified by immunohistochemistry. Conclusions: We conclude that chronic inflammation alters the gene expression patterns in muscle of untreated children with JDM. Symptoms lasting greater or equal to 2 months were associated with dendritic cell maturation and anti-angiogenic vascular remodelling, directly contributing to disease pathophysiology. Experiment Overall Design: After obtaining informed consent, 23 girls with definite JDM were enrolled in this study prior to obtaining the MRI directed diagnostic muscle biopsy. All 23 JDM samples and 4 healthy age- and sex-matched controls were expression profiled and for first gene filtering. Only profiling data from untreated patients (19 profiles) were then analyzed statistically. Experiment Overall Design: disease duration : less than 2 months: YJD-JDM-2UA-s2,YJD-JDM-1UA-s2,YJD-JDM-16UA-s2 Experiment Overall Design: disease duration : more than 2 months:YJD-JDM-30UA-s2,YJD-JDM-19UA-s2,YJD-JDM-5UA-s2,YJD-JDM-21UA-s2,YJD-JDM-18UA-s2,YJD-JDM-3UA-s2,YJD-JDM-23UA-s2,YJD-JDM-9UA-S2,YJD-JDM-12UA-s2,YJD-JDM-14UA-s2,YJD-JDM-25UA-s2,YJD-JDM-8UA-s2,YJD-JDM-15UA-s2,YJD-JDM-13UA-s2,YJD-JDM-10UA-S2,YJD-JDM-6UA-s2.
2008-10-21 | E-GEOD-11971 | biostudies-arrayexpress
Project description:Background :To evaluate the impact of the duration of chronic inflammation on gene expression in skeletal muscle biopsies (MBx) from untreated children with juvenile dermatomyositis (JDM) and identify genes and biological processes associated with the disease progression, expression profiling data from 16 girls with active symptoms of JDM greater or equal to 2 months were compared with 3 girls with active symptoms less than 2 months. Results: Seventy-nine genes were differentially expressed between the groups with long or short duration of untreated disease. Genes involved in immune responses and vasculature remodeling were expressed at a higher level in muscle biopsies from children with greater or equal to 2 months of symptoms, while genes involved in stress responses and protein turnover were expressed at a lower level. Among the 79 genes, expression of 9 genes showed a significant linear regression relationship with the duration of untreated disease. Five differentially expressed genes--HLA-DQA1, smooth muscle myosin heavy chain, clustering, plexin D1 and tenomodulin--were verified by quantitative RT-PCR. The chronic inflammation of longer disease duration was also associated with increased DC-LAMP+ and BDCA2+ mature dendritic cells, identified by immunohistochemistry. Conclusions: We conclude that chronic inflammation alters the gene expression patterns in muscle of untreated children with JDM. Symptoms lasting greater or equal to 2 months were associated with dendritic cell maturation and anti-angiogenic vascular remodelling, directly contributing to disease pathophysiology. Keywords: Disease progression; time course
2008-07-18 | GSE11971 | GEO
Project description:Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is a systemic vasculopathy affecting young children. Epidemiology studies documenting an antecedent illness in the 3 mo before the first definite symptom (rash and/or weakness) of JDM are supported by immunologic data that suggest that the disease pathophysiology is Ag driven. The purpose of this study was to compare the gene expression profiles in muscle biopsies of four untreated DQA1*0501(+) JDM children with profiles from children with a known necrotizing myopathy (Duchenne muscular dystrophy), as well as an in vitro antiviral model (NF90), and healthy pediatric controls. Nearly half (47%) of the dysregulated genes in JDM were associated with the immune response. In particular, increased expression of IFN-alphabeta-inducible genes 6-16, myxovirus resistance protein p78, latent cytosolic transcription factor, LMP2, and TAP1 was observed. This profile is consistent with an IFN-alphabeta transcription cascade seen in the in vitro viral resistance model. The IFN-alphabeta-inducible profile was superimposed on transcription profiles reflective of myofiber necrosis and regeneration shared with Duchenne muscular dystrophy. Expressed genes were confirmed by quantitative real-time PCR (6-16), immunofluorescence (thrombospondin 4), and immunolocalization (IFN-gamma, p21). Keywords: other
2003-07-16 | GSE493 | GEO
Project description:Juvenile dermatomyositis (JDM) is a rare autoimmune condition with insufficient biomarkers and treatments, in part, due to incomplete knowledge of the cell types mediating disease. We investigated immunophenotypes and cell-specific genes associated with disease activity using multiplexed RNA and protein single-cell sequencing applied to PBMCs from 4 treatment-naïve JDM (TN-JDM) subjects at baseline, 2, 4, and 6 months and 4 subjects with inactive disease.
2022-04-30 | GSE190684 | GEO
Project description:To better understand the pathogenesis of juvenile dermatomyositis (JDM) we examined the genetic alterations that result from exogenous IFN I exposure in pediatric skeletal muscle. We compared untreated healthy pediatric donor-derived myobundles with those treated with IFN I as well as with JAKi baricitinib and tofacitinib. We used bulk mRNA sequencing to evaluate how IFN I and treatment with JAKi influence healthy and JDM skeletal muscle gene expression and show IFNβ leads to a greater pro-inflammatory gene response than IFNα in pediatric skeletal muscle. As a type I interferon gene signature is established in JDM, downregulated oxidative phosphorylation, myogenesis, and contractile protein gene expression is implicated in JDM pathology. These genetic changes are partially reversed by JAK inhibitors, baricitinib and tofacitinib, with baricitinib leading to greater genetic alteration than tofacitinib. Our findings show that analysis of differential gene expression in bioengineered pediatric skeletal muscle can inform our knowledge of JDM pathogenesis and therapeutic effects.
2024-09-18 | GSE243339 | GEO
Project description:Skeletal muscle is highly vascularized. Beyond oxygen and nutriment supply, new functions for vessels have been recently identified, via the interactions that vessel cells establish with muscle progenitor cells. These latter cells closely interact with endothelial cells for their expansion and their differentiation, while periendothelial cells are involved in muscle cell self-renewal and return to quiescence. Thus, vessels play a central role in the tissue remodeling after an injury, while the mechanisms are poorly understood. We investigated myogenic/endothelial cell (MPCs/ECs) interactions in two paradigmatic contexts of regenerating muscle in the child: Juvenile Dermatomyositis (JDM), which is characterized by a transient loss of capillaries, and Duchenne Muscular Dystrophy (DMD), which is associated with an increase in vessel density. We showed in vitro specific interactions between myoblasts isolated from muscle of JDM and DMD patients and endothelial cells. In vitro myogenesis/angiogenesis studies demonstrated that MPCs exhibited various angiogenic properties depending on the pathological environment. In DMD, MPCs promoted the development of an anarchic, although strong, ECs stimulation, leading to the formation of weakly functional vessels. DMD cells presented an unbalanced homeostasis with nonspecific deregulation of several processes involved in muscle and vessel development. On the contrary, in JDM, MPCs enhanced the vessel reconstruction to efficiently restore the vessel function via the expression of a set of specific angiogenic effectors. MPCs exhibit a strong specific type I IFNs signature and ECs a dysregulation of their angiogenic capacities, suggesting a drastic reprogrammation of these cells in response to an inflammatory environment during JDM.
2017-07-27 | GSE66845 | GEO
Project description:BackgroundJuvenile dermatomyositis (JDM) is a systemic vasculopathy associated with metabolic derangements and possible increased risk for premature atherosclerosis. Oxidation of low-density lipoprotein (LDL) in the endothelium is an early step in atherosclerotic plaque formation. It is not known if oxidized LDL is altered in children with untreated JDM. The deposition of oxidized LDL in the vasculature of muscle biopsies (MBx) from patients with untreated JDM and pediatric controls was assessed.FindingsFrozen tissue sections of MRI-directed MBx from 20 female children with untreated JDM and 5 female controls were stained with DAPI and fluorescently labeled antibodies against von Willebrand factor (vWF) and LDL oxidized by copper (oxLDL). Blood vessels were identified by positive vWF staining, and total fluorescence of oxLDL within the vessel walls was measured. Children with untreated JDM had increased deposition of oxLDL in the walls of muscle vasculature compared to healthy children (difference in means ± SEM = 19.86 ± 8.195, p = 0.03). Within the JDM cohort, there was a trend towards increased oxLDL deposition with longer duration of untreated disease (r = 0.43, p = 0.06). There was no significant correlation found between oxLDL deposition and markers of acute JDM disease activity including disease activity scores or muscle enzymes.ConclusionsThis study found increased deposition of oxLDL within blood vessels of children with untreated JDM supporting the concern that these children are at increased risk for premature atherosclerosis from chronic exposure to vascular oxLDL. This study highlights the importance of early diagnosis and treatment initiation to ameliorate cardiovascular damage.
| S-EPMC11308466 | biostudies-literature
Project description:RNA sequencing was used to compare the transcriptional state of ex-vivo B-cells from children with Juvenile dermatomyositis (JDM) pre- and on-treatment and age-matched healthy controls. RNA was extracted from blood samples that were taken from juvenile dermatomyositis patients at diagnosis (before they received treatment) and approximately a year into treatment. The treatment included oral prednisolone, methotrexate, azathioprine, cyclophosphamide and other drugs.
2019-01-03 | E-MTAB-5616 | biostudies-arrayexpress
Project description:INTRODUCTION:The aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood. In particular the contribution of monocytes or macrophages, which are frequently observed to be an infiltrate within muscle tissue very early in the disease process, is unknown. We hypothesised that these cells secrete the pro-inflammatory myeloid related protein (MRP) 8/14 which may then contribute to muscle pathology in JDM. METHODS:In this study of 56 JDM patients, serum MRP8/14 levels were compared with clinical measures of disease activity. Muscle biopsies taken early in disease were assessed by immunohistochemistry to determine the frequency and identity of MRP-expressing cells. The effects of MRP stimulation and endoplasmic reticulum (ER) stress on muscle were tested in vitro. Serum or supernatant levels of cytokines were analyzed by multiplex immunoassay. RESULTS:Serum MRP8/14 correlated with physician's global assessment of disease activity in JDM (R = 0.65, p = 0.0003) and muscle strength/endurance, childhood myositis assessment score (CMAS, R = -0.55, p = 0.004). MRP8/14 was widely expressed by CD68+ macrophages in JDM muscle tissue. When cultured with human myoblasts, MRP8 led to the secretion of MCP-1 and IL-6, which was enhanced by ER stress. Both inflammatory mediators were detected in significantly higher levels in the serum of JDM patients compared to healthy controls. CONCLUSIONS:This study is the first to identify serum MRP8/14 as a potential biomarker for disease activity in JDM. We propose that tissue infiltrating macrophages secreting MRP8/14 may contribute to myositis, by driving the local production of cytokines directly from muscle.
| S-EPMC3978554 | biostudies-literature
Project description:RNA sequencing was used to compare the transcriptional state of ex-vivo B-cells, moncytes and T-cells from children with Juvenile dermatomyositis (JDM) pre- and on-treatment and age-matched healthy controls. RNA was extracted from blood samples that were taken from juvenile dermatomyositis patients at diagnosis (before they received treatment) and approximately a year into treatment. The treatment included oral prednisolone, methotrexate, azathioprine, cyclophosphamide and other drugs.
2022-12-31 | GSE221091 | GEO