Abstract
Enteroviruses (EVs) have long been implicated in the pathogenesis of type 1 diabetes (T1D), and accumulating evidence has associated virus-induced autoimmunity with the loss of pancreatic beta cells in T1D. Inflammatory cytokines including interferons (IFN) form a primary line of defence against viral infections, and their chronic elevation is a hallmark feature of many autoimmune diseases. IFNs play a key role in activating and regulating innate and adaptive immune responses, and to do so they modulate the expression of networks of genes and transcription factors known generically as IFN stimulated genes (ISGs). ISGs in turn modulate critical cellular processes ranging from cellular metabolism and growth regulation to endoplasmic reticulum (ER) stress and apoptosis. More recent studies have revealed that IFNs also modulate gene expression at an epigenetic as well as post-transcriptional and post-translational levels. As such, IFNs form a key link connecting the various genetic, environmental and immunological factors involved in the initiation and progression of T1D. Therefore, gaining an improved understanding of the mechanisms by which IFNs modulate beta cell function and survival is crucial in explaining the pathogenesis of virally-induced T1D. This should provide the means to prevent, decelerate or even reverse beta cell impairment.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by reduced insulin production and caused by a specific immune-mediated loss of insulin producing beta cells [1,2]
Marroqui et al showed that IFNα induces human leukocyte antigen class I (HLA-I) and markers of endoplasmic reticulum (ER) stress such as Binding Immunoglobulin Protein (BIP), C/EBP Homologous Protein (CHOP), Activating Transcription Factor 3 (ATF3) and spliced X-box Binding Protein 1 (XBP1s) in the human beta cell line EndoC-βH1
The pro-apoptotic and virus-activating effects of Jun N-terminal kinase 1 (JNK1) were regulated independently. These findings suggest that IRE1α-induced JNK1 activation may be required for efficient Coxsackievirus B (CVB) replication in pancreatic beta cells
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by reduced insulin production and caused by a specific immune-mediated loss of insulin producing beta cells [1,2]. Marroqui et al showed that IFNα induces HLA-I and markers of ER stress such as Binding Immunoglobulin Protein (BIP), C/EBP Homologous Protein (CHOP), Activating Transcription Factor 3 (ATF3) and spliced X-box Binding Protein 1 (XBP1s) in the human beta cell line EndoC-βH1 They found similar responses in the islets of people with recent-onset T1D [91,92]. Enteroviruses depend on internal ribosome entry sites (IRES) to mediate protein translation and replication, and it has been shown that eIF2α is required for IRES-dependent translation initiation [106] These findings suggest that some EVs have evolved to take advantage of the selective UPR response occurring in beta cells during infection, but how they achieve this and what role IFNs play are still an open question
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