Myositis is characterized clinically by skeletal muscle weakness and histopathologically by the presence of inflammatory cells in muscle tissue. There are several major subclasses of myositis, including dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), and immune mediated necrotizing myopathy (NM). The leukocyte infiltration present in myositis muscle is believed to contribute to disease pathogenesis [1–5]. The types of immune cells present in myositis muscle were originally identified in the 1980s as predominantly CD4+ T cells and B cells in DM, and CD4+ and CD8+ T cells in IBM [1, 6–8], with more recent identification of plasmacytoid dendritic cells in DM , myeloid dendritic cells in PM and IBM , and plasma cells in all three disorders . Unlike DM, PM or IBM, NM is characterized by myofiber necrosis associated with macrophages and minimal T cell infiltration or MHC Class I expression . Given the differences in clinical manifestations between these subtypes of myositis and the lack of optimal efficacious therapies for these diseases, understanding the molecular characteristics underlying their subtypes may facilitate the development of novel therapeutics that could benefit patients with myositis.
Technologies such as whole genome microarray have advanced our understanding of the disease pathogenesis of myositis [11–13]. A large number of type 1 interferon-stimulated genes (ISGs) were identified to be strongly overexpressed in DM muscle and this molecular signature has been further confirmed by recent studies [4, 14]. The activation of type 1 interferon (IFN) signaling has been observed in many autoimmune diseases [15, 16], such as systemic lupus erythematosus (SLE) [17–19], systemic sclerosis , rheumatoid arthritis , and psoriasis . A type 1 IFN signature is not only present in DM muscle but also expressed in DM skin , as well as peripheral blood of DM and PM, reflecting disease activity [24–26]. Based on the accumulating evidence from recent microarray studies and other complementary experiments, disease models have been proposed to emphasize the central role of type 1 IFN pathway activation in the pathogenesis of DM, suggesting that blockade of type 1 IFN might provide clinical benefit to DM patients .
In addition to previous studies focused on altered mRNA expression in myositis, the roles of microRNAs (miRNAs) in regulating immune responses, muscle development, and regeneration are also emerging [28–31]. miRNAs including miR-146a, miR-155, and miR-101 have been shown to be aberrantly expressed in rheumatic diseases [32–35] and miR-1, miR-133a/b, and miR-206 have been identified as muscle-specific miRNAs critical for muscle development and function [28–31]. Though the role of miRNAs in the pathogenesis of myositis has yet to be evaluated extensively, it is worth noting that interactions between miRNAs and type 1 IFN have been identified . Specifically, miR-146a suppresses the innate immune response not only via the TLR-mediated NFκB pathway , but also negatively regulates the type 1 IFN pathway in SLE by targeting STAT1 and IFN regulatory factor 5 (IRF5) .
Despite the aforementioned studies, there still lacks a clear understanding of the disease pathogenesis that underlies myositis. Meanwhile, few molecular biomarkers have been identified to aid in stratifying myositis patients or objectively quantifying the leukocyte abundance in inflammatory muscle and the corresponding muscle fiber damage. To address the unmet needs in these areas, we performed both genome-wide mRNA and miRNA expression profiling in muscle biopsies from myositis patients and normal controls. Our studies revealed gene expression signatures specific for myositis and distinct for each subclass of myositis, as well as multiple pairs of mRNA:miRNA displaying anti-correlation expression patterns in line with predicted relationships. Additionally, expression data from this study indicated that miR-146a displayed a positive correlation with the type 1 IFN signature rather than the expected negative correlation in myositis muscle. We postulated that such positive correlation could be driven by infiltrated leukocytes; therefore, we developed an invasion model to account for transcriptional changes due to leukocyte infiltration. Further analyses with this invasion model indicated that the source of ISG expression may differ between subtypes of myositis, such that in PM and IBM, ISG expression is associated with infiltrated leukocytes, whereas in DM, non-leukocyte cells (e.g., muscle cells) might contribute significantly to ISG expression. Collectively, our results revealed multiple gene expression signatures that can potentially advance our understanding of the pathologic characteristics of myositis and provide utility as molecular biomarkers for identifying the right therapeutics for myositis patients.