Type 1 Diabetes: Interferons and the Aftermath of Pancreatic Beta-Cell Enteroviral Infection

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.

Keywords: Endoplasmic Reticulum (ER) stress; Interferon Stimulated Genes (ISG); apoptosis; autoimmune disease; enterovirus; innate immunity.

Figure 1

Virus-induced autoimmune T1D. An initial enterovirus (EV) infection activates pattern recognition receptors (PRRs) that induce interferons (IFNs) and interferon stimulated genes (ISGs) as well as PRRs that directly target and cleave viral RNA, driving a collective intrinsic antiviral response that may lead to virus clearance or virus persistence. The surge in IFNs and ISGs promotes Endoplasmic Reticulum (ER) stress and unfolded protein response (UPR) which, alone or in combination with virus infection, may lead to programmed cell death (apoptosis), exposing virus and self-antigens to the immune system. In addition, IFNs promote antigen presentation and immune cell migration by inducing the expression of human leukocyte antigen class I (HLA-I) molecules and chemokines such as C-X-C motif chemokine 10 (CXCL10). Cells with lytic or persistent infection that do not undergo apoptosis may present viral antigens (e.g., VP1) and self-antigens (including neo-antigens induced by IFNs and UPR) to the immune cells (APCs, CD8+ and CD4+ T cells) leading to development of autoantibodies and an adaptive autoimmune response against antigen producing cells. Islet infiltrating immune cells may also contribute to ER stress and UPR in beta cells by releasing inflammatory cytokines such as IFNα and IFNγ. MDA5, melanoma differentiation-associated protein 5; PKR, protein kinase R; VP1, virus capsid protein 1.