Identification of distinctive interferon gene signatures in different types of myositis

Abstract

ObjectiveActivation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies.MethodsThe expression of IFN1- and IFN2-inducible genes was compared between the different groups.ResultsThe expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies.ConclusionsIFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

239th ENMC International Workshop: Classification of dermatomyositis, Amsterdam, the Netherlands, 14–16 December 2018

“…However, this pathologic finding was never observed in DM patients with anti-NXP2 autoantibodies. Despite these histological differences in muscle biopsy features, Dr. Mammen presented preliminary data from gene expression profiling studies demonstrating that anti-NXP2 muscle tissue has a prominent type I interferon signature that is indistinguishable from patients with other DM-specific autoantibodies [13] .…”

Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis

“…To classify biopsies as IMNM, linear SVM relied on the relative underexpression of genes expressed at high levels in other forms of myositis (eg, STAT1 and PSMB8) 15 rather than on genes that were uniquely overexpressed in IMNM. To further investigate pathological processes important for IMNM, we considered the known functions of the top 10 overexpressed genes in biopsies from these patients (table 4).…”

Distinct tissue injury patterns in juvenile dermatomyositis auto-antibody subgroups

“…Mi-2 autoantibody may preferentially bind to myofibers, while NXP-2 and TIF1γ autoantibodies may preferentially bind to capillaries. Activation of these various receptors all result in upregulation of the interferon (IFN) pathway genes [35], and downstream complement pathway activation.…”