Expression of the OAS Gene Family Is Highly Modulated in Subjects Affected by Juvenile Dermatomyositis, Resembling an Immune Response to a dsRNA Virus Infection

Abstract

Background: Juvenile dermatomyositis (JDM) is a systemic, autoimmune, interferon (IFN)-mediated inflammatory muscle disorder that affects children younger than 18 years of age. JDM primarily affects the skin and the skeletal muscles. Interestingly, the role of viral infections has been hypothesized. Mammalian 2′-5′-oligoadenylate synthetase (OAS) genes have been thoroughly characterized as components of the IFN-induced antiviral system, and they are connected to several innate immune-activated diseases. The main purpose of the paper is to define the potential interrelationship between the OAS gene family network and the molecular events that characterize JDM along with double-stranded RNA (dsRNA) molecular pathways. Methods: We analyzed three microarray datasets obtained from the NCBI in order to verify the expression levels of the OAS gene family network in muscle biopsies (MBx) of JDM patients compared to healthy controls. Furthermore, From GSE51392, we decided to select significant gene expression profiles of primary nasal and bronchial epithelial cells isolated from healthy subjects and treated with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA), a molecular pattern associated with viral infection. Results: The analysis showed that all OAS genes were modulated in JDM muscle biopsies. Furthermore, 99% of OASs gene family networks were significantly upregulated. Of importance, 39.9% of modulated genes in JDM overlapped with those of primary epithelial cells treated with poly(I:C). Moreover, the microarray analysis showed that the double-stranded dsRNA virus gene network was highly expressed. In addition, we showed that the innate/adaptive immunity markers were significantly expressed in JDM muscles biopsies. and that their levels were positively correlated to OAS gene family expression. Conclusion: OAS gene expression is extremely modulated in JDM as well as in the dsRNA viral gene network. These data lead us to speculate on the potential involvement of a viral infection as a trigger moment for this systemic autoimmune disease. Further in vitro and translational studies are needed to verify this hypothesis in order to strategically plan treatment interventions.

Peer Review #2 of "Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis (v0.1)"

“…In the present study, we found that interferon-stimulated genes were significantly upregulated in JDM patients, as well as the so-called "interferon signature", demonstrating a possible mechanism that viral mimics or other stimuli may play a crucial role in the pathogenesis of JDM. Viral mimics are thought to participate in the pathogenesis of JDM (Musumeci & Castrogiovanni 2018) and other autoimmune diseases (Christen et al 2004;Sellami et al 2019), consistent with the notion that JDM patients have higher rates of viral infections (Tansley et al 2013;Zheng et al 2019). This may suggest that the prevention of certain viral infections would decrease the incidence of autoimmunity by inhibiting self-antigenic mimics.…”

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

“…In the present study, we found that interferon-stimulated genes were significantly upregulated in JDM patients, as well as the so-called ''interferon signature'', demonstrating a possible mechanism that viral mimics or other stimuli may play a crucial role in the pathogenesis of JDM. Viral mimics are thought to participate in the pathogenesis of JDM (Musumeci & Castrogiovanni, 2018) and other autoimmune diseases (Christen et al, 2004;Sellami et al, 2019), consistent with the notion that JDM patients have higher rates of viral infections (Tansley, McHugh & Wedderburn, 2013;Zheng et al, 2019). This may suggest that the prevention of certain viral infections would decrease the incidence of autoimmunity by inhibiting self-antigenic mimics.…”

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

“…Moreover, the IFNG signaling pathways were significantly involved through the expression of 23 genes out of 189 available (p = 5.19 × 10 −22 , 12.1%) ( Figure 1d) ( Supplementary Table S1). In our analysis, we also observed several antiviral response activated pathways, such as the double-strand RNA virus (OAS1, OAS2 and OAS3) (three out of nine genes; p = 0.00066, 33.3%) [40][41][42][43][44], the Herpes simplex (14 out of 181 genes; p = 1.10 × 10 −10 , 7.7%), and Influenza A virus (10 out 168 genes; p = 5.29 × 10 −7 , 5.9%) ( Supplementary Table S1). These specific activated pathways could be due to the IFNG signaling.…”