From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies

Abstract

Objective. Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology.Methods. The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed.Results. ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing.Conclusion. Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.

Morphological Characteristics of Idiopathic Inflammatory Myopathies in Juvenile Patients

“…However, steroid resistance in some patients results in poor prognosis and warrants new therapeutic strategies [ 28 ]. IFN-related endothelial injury and Janus kinase (JAK) inhibition has emerged as a novel therapeutic strategy in difficult-to-treat cases [ 1 , 29 , 30 ].…”

Identification of Vital Hub Genes and Potential Molecular Pathways of Dermatomyositis by Bioinformatics Analysis

“…ISG15 is an IFN- α / β -inducible, intracellular ubiquitin-like protein. Related studies have shown that the level of ISG15 is negatively correlated with the severity of muscle histological damage and positively correlated with exercise capacity (CMAS, MMT) [ 36 , 37 ]. In addition, for the diagnosis of juvenile DM, the expression of muscle ISG15 is closely related to juvenile DM and may be a potential biomarker for the diagnosis of juvenile DM [ 37 ].…”

“…Related studies have shown that the level of ISG15 is negatively correlated with the severity of muscle histological damage and positively correlated with exercise capacity (CMAS, MMT) [ 36 , 37 ]. In addition, for the diagnosis of juvenile DM, the expression of muscle ISG15 is closely related to juvenile DM and may be a potential biomarker for the diagnosis of juvenile DM [ 37 ]. In recent years, the description of ISG15 as a central participant in host antiviral response has been widely accepted, and ISG15 could protect and limit the damage to human tissues caused by the viral response through the participation and regulation of the type I interferon signaling pathway.…”

Inflammatory myopathies in childhood

“…In their report, Dubowitz and colleagues discuss their negative staining results of interferons alpha, beta and gamma that had been mentioned to occur by Isenberg 1986. Nowadays we know that it is feasible to detect type I interferon-related gene expression in jDM muscle with certain modern techniques even in different serological subtypes of jDM [27] . Victor Dubowitz' pioneering work on MHC class I expression in DMD and in child inflammatory myopathy as well as in other neuromuscular diseases dates from 1984 and was published in the Lancet [28] .…”

“…The levels of expression of ISGs that promote IFN-I signalling (IFIH1, DDX58) were remarkably similar amongst JDM patients whatever the MSAs. Conversely, an inverse correlation between the expression levels of the IFN-I signalling regulator ISG15 in the muscle and the severity of muscle involvement were identified [27] . These results suggest that the individual ability of muscle resident cells to control the response to IFN-I is a key factor for determining disease progression.…”