Muscle Expression of Type I and Type <scp>II</scp> Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

Moneta, Gian Marco; Marafon, Denise Pires; Marasco, Emiliano; Rosina, Silvia; Verardo, Margherita; Fiorillo, Chiara; Minetti, Carlo; Bracci-Laudiero, Luisa; Ravelli, Angelo; Benedetti, Fabrizio; Nicolai, Rebecca

doi:10.1002/art.40800

Cited by 62 publications

(44 citation statements)

References 35 publications

(46 reference statements)

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“…However, few of them were identified as biomarkers or crucial genes in JDM yet. Functional enrichment analysis indicated that type I interferon signaling and various virus infection pathways were strengthened in JDM compared to HC, which is consistent with findings of previous studies (Moneta, Marafon & Marasco, 2019;Piper et al, 2018). IFIT5, IFI16 and MX2, interferon-stimulated genes, both nuclear transcriptional factors, were found to be upregulated in other autoimmune diseases but not in JDM (Wang et , 2019b;Zhang & Xu, 2019).…”

Section: Discussionsupporting

confidence: 87%

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Zhong

Bai

et al. 2020

PeerJ

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Background. Juvenile dermatomyositis (JDM) is an immune-mediated disease characterized by chronic organ inflammation. The pathogenic mechanisms remain ill-defined. Methods. Raw microarray data of JDM were obtained from the gene expression omnibus (GEO) database. Based on the GSE3307 dataset with 39 samples, weighted correlation network analysis (WGCNA) was performed to identify key modules associated with pathological state. Functional enrichment analyses were conducted to identify potential mechanisms. Based on the criteria of high connectivity and module membership, candidate hub genes were selected. A protein-protein interaction network was constructed to identify hub genes. Another dataset (GSE11971) was used for the validation of real hub genes. Finally, the real hub genes were used to screen out smallmolecule compounds via the Connectivity map database. Results. Three modules were considered as key modules for the pathological state of JDM. Functional enrichment analysis indicated that responses to interferon and metabolism were dysregulated. A total of 45 candidate hub genes were selected according to the pre-established criteria, and 20 genes could differentiate JDM from normal controls by validation of another external dataset (GSE11971). These real hub genes suggested the pivotal role of mitochondrial dysfunction and interferon signature in JDM. Furthermore, drug repositioning highlighted the importance of acacetin, helveticoside, lanatoside C, deferoxamine, LY-294002, tanespimycin and L01AD from downregulated genes with the potential to perturb the development of JDM, while betonicine, felodipine, valproic acid, trichostatin A and sirolimus from upregulated genes provided potentially therapeutic goals for JDM. Conclusions. There are 20 real hub genes associated with the pathological state of JDM, suggesting the pivotal role of mitochondrial dysfunction and interferon signature in JDM. This analysis predicted several kinds of small-molecule compounds to treat JDM. Q. 2020. Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis. PeerJ 8:e8611 http://doi.Burrows FJ, Fritz LC, Feinstein DL. 2006. The heat-shock protein 90 inhibitor 17allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. Journal of Neurochemistry Drinkard BE, Hicks J, Danoff J, Rider LG. 2003. Fitness as a determinant of the oxygen uptake/work rate slope in healthy children and children with inflammatory myopathy. Canadian Journal of Applied Physiology 28:888-897 DOI 10.1139/h03-063. Feldman BM, Rider LG, Reed AM, Pachman LM. 2008. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. . 2016. Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis. Rheumatology 55:470-479 DOI 10.1093/rheumatology/kev359. Greenberg SA. 2010. Dermatomyositis and type 1 interferons. Current Rheumatology

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Section: Discussionsupporting

confidence: 87%

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Zhong

Bai

et al. 2020

PeerJ

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“…The first IFN module was stable over the disease course and consisted of genes induced primarily by type I IFN, whereas the second and third IFN modules correlated with skin and renal disease activity, and the genes in these modules were equally induced by both types I and II IFN, suggesting a role for type II IFN in SLE. In juvenile DM, IFN‐γ transcripts have been identified in the muscle tissue of 11 untreated patients and co‐localized with inflammatory infiltrates and T cells . However, the role of type II IFN in DM has not been thoroughly explored using unbiased, data‐driven methods.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Meta‐Analysis Reveals Concordance in Gene Activation, Pathway, and Cell‐Type Enrichment in Dermatomyositis Target Tissues

Neely

Rychkov

Paranjpe

et al. 2019

ACR Open Rheumatology

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Objective. We conducted a comprehensive gene expression meta-analysis in dermatomyositis (DM) muscle and skin tissues to identify shared disease-relevant genes and pathways across tissues.Methods. Six publicly available data sets from DM muscle and two from skin were identified. Meta-analysis was performed by first processing data sets individually then cross-study normalization and merging creating tissue-specific gene expression matrices for subsequent analysis. Complementary single-gene and network analyses using Significance Analysis of Microarrays (SAM) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify genes significantly associated with DM. Cell-type enrichment was performed using xCell.Results. There were 544 differentially expressed genes (FC ≥ 1.3, q < 0.05) in muscle and 300 in skin. There were 94 shared upregulated genes across tissues enriched in type I and II interferon (IFN) signaling and major histocompatibility complex (MHC) class I antigen-processing pathways. In a network analysis, we identified eight significant gene modules in muscle and seven in skin. The most highly correlated modules were enriched in pathways consistent with the singlegene analysis. Additional pathways uncovered by WGCNA included T-cell activation and T-cell receptor signaling. In the cell-type enrichment analysis, both tissues were highly enriched in activated dendritic cells and M1 macrophages.Conclusion. There is striking similarity in gene expression across DM target tissues with enrichment of type I and II IFN pathways, MHC class I antigen-processing, T-cell activation, and antigen-presenting cells. These results suggest IFN-γ may contribute to the global IFN signature in DM, and altered auto-antigen presentation through the class I MHC pathway may be important in disease pathogenesis.

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“…As we know, an IFN signature has previously been described to be elevated in dermatomyositis [42,43]. Because neopterin is produced in response to IFN-γ, the high level of neopterin in DM patients may represent an IFN response.…”

Section: Discussionmentioning

confidence: 99%

A high level of serum neopterin is associated with rapidly progressive interstitial lung disease and reduced survival in dermatomyositis

Peng

Zhang

Liang

et al. 2019

Clinical and Experimental Immunology

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Summary Neopterin is primarily synthesized and released by activated macrophages/monocytes upon stimulation with interferon‐γ and is considered as a marker for macrophage activation. This study aimed to analyze the serum levels of neopterin in patients with dermatomyositis (DM) in association with clinical manifestations, laboratory data and patient prognosis. One hundred and eighty‐two consecutive DM patients and 30 healthy controls were retrospectively enrolled into the study. Serum levels of neopterin were significantly increased in DM patients compared to healthy controls (P < 0·001). High serum neopterin levels were associated with anti‐melanoma differentiation‐associated gene (MDA5) antibody, rapidly progressive interstitial lung disease (RP‐ILD) and characteristic DM cutaneous involvement. Longitudinal assessment of serum samples revealed that the serum neopterin levels were closely correlated with disease severity (β = 30·24, P < 0·001). In addition, a significant increase in serum neopterin concentration of non‐survivors was observed when compared to that of survivors (P < 0·001). Receiver operator characteristic curves showed that serum neopterin could distinguish non‐survivors and survivors at an optimal cut‐off level of 22·1 nmol/l with a sensitivity and specificity of 0·804 and 0·625, respectively (P < 0·001). Kaplan–Meier survival curves revealed that DM patients with serum neopterin > 22·1 nmol/l had a significantly higher mortality compared to the patient group with serum neopterin < 22·1 nmol/l (log‐rank P < 0·001). Multivariate regression analysis identified high serum neopterin concentration to be an independent risk factor for poor prognosis in DM (adjusted hazard ratio = 4·619, 95% confidence interval = 2·092–10·195, P < 0·001). In conclusion, increased serum levels of neopterin were significantly associated with RP‐ILD and reduced survival in DM patients, suggesting it as a promising biomarker in disease evaluation of DM.

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Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

Cited by 62 publications

References 35 publications

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Gene Expression Meta‐Analysis Reveals Concordance in Gene Activation, Pathway, and Cell‐Type Enrichment in Dermatomyositis Target Tissues

A high level of serum neopterin is associated with rapidly progressive interstitial lung disease and reduced survival in dermatomyositis

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