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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.

International audience; What is already known about this subject? ► among inflammatory/dysimmune myopathies (iDMs), dermatomyositis (DM) is the only associated with type i-interferon signature. ► Most iDMs are associated with myofiber expression of major histocompatibility complex (MHc)-class i. MHc-i is induced by interferons suggesting a possible role for type ii-interferon in iDMs other than DM. What does this study add? ► in this study, we showed that myofiber MHc-ii expression is observed in inclusion body myositis (iBM) and antisynthetase myositis (aSM), but not in DM and necrotizing autoimmune myopathy (naM). ► in accordance with this finding, we showed that iBM and aSM are specifically associated with type-ii iFnγ signature, DM only with type-i iFn signature, and naM with neither type-i nor type-ii iFn signature. How might this impact on clinical practice? ► Distinct iFn signatures allow a more distinct segregation of iDMs and therefore a more accurate diagnosis. ► Deciphering iFn signatures in iDMs will also lead to develop new therapeutic approaches targeting iFns pathways. AbstrAct Objective the role of interferons (iFn) in the pathophysiology of primary inflammatory and dysimmune myopathies (iDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. in present work we analysed the muscular expression of specific iFnα/β and iFnγ-stimulated genes in patients with various types of iDM. Methods 39 patients with iDM with inclusion body myositis (iBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (naM, n=10) and antisynthetase myositis (aSM, n=10), and 10 controls were included. Quantification of expression levels of iFnγ, iSg15, an iFnα/β-inducible gene and of six iFnγ-inducible genes (gBP2, Hla-DOB, Hla-DPB, ciita, Hla-DrB and Hla-DMB) was performed on muscle biopsy samples. Results DM usually associated with strong type i iFnα/β signature, iBM and aSM with prominent type ii iFnγ signature and naM with neither type i nor type ii iFn signature. immunofluorescence study in aSM and iBM showed myofibre expression of major histocompatibility class 2 (MHc-2) and ciita, confirming the induction of the iFnγ pathway. Furthermore, MHc-2-positive myofibres were observed in close proximity to cD8+ t cells which produce high levels of iFnγ. Conclusion Distinct iFn signatures allow a more distinct segregation of iDMs and myofibre MHc-2 expression is a reliable biomarker of type ii iFn signature.

Tutorial for the quantification of muscle fiber morphometry using the macroIMRB. (DOCX 2541 kb)

Tutorial for the quantification of muscle fiber morphometry using the macroIMRB. (DOCX 2541 kb)