Viral infections in type 1 diabetes mellitus--why the β cells?

Abstract

Type 1 diabetes mellitus (T1DM) is caused by progressive autoimmune-mediated loss of pancreatic β-cell mass via apoptosis. The onset of T1DM depends on environmental factors that interact with predisposing genes to induce an autoimmune assault against β cells. Epidemiological, clinical and pathology studies in humans support viral infection--particularly by enteroviruses (for example, coxsackievirus)--as an environmental trigger for the development of T1DM. Many candidate genes for T1DM, such as MDA5, PTPN2 and TYK2, regulate antiviral responses in both β cells and the immune system. Cellular permissiveness to viral infection is modulated by innate antiviral responses that vary among different tissues or cell types. Some data indicate that pancreatic islet α cells trigger a more efficient antiviral response to infection with diabetogenic viruses than do β cells, and so are able to eradicate viral infections without undergoing apoptosis. This difference could account for the varying ability of islet-cell subtypes to clear viral infections and explain why chronically infected pancreatic β cells, but not α cells, are targeted by an autoimmune response and killed during the development of T1DM. These issues and attempts to target viral infection as a preventive therapy for T1DM are discussed in the present Review.

Figure 1. Regulation of key antiviral responses in pancreatic β cells

Following infection, replicating coxsackievirus subtype B (CVB) produce cytosolic double-stranded RNA (dsRNA), a nonphysiological form of mRNA recognized by the cytoplasmic receptor MDA5. Binding of MDA5 to the dsRNA activates the transcription factors NF-κB, IRFs and STATs, triggering production of type I interferons and chemokines, thus contributing to local inflammation (insulitis). Type I interferons (IFN-α and IFN-β), type II interferon (IFN-γ) and the cytokines TNF and IL-1β contribute to β-cell destruction among genetically susceptible individuals. Type I interferons bound to the IFN-α/β receptor (IFNAR) signal via TYK2 and JAK1 and induce activation of STATs and expression of interferon-stimulated genes (ISGs) with antiviral properties. Proinflammatory cytokines promote the activation of JNK1, which induces the intrinsic (mitochondrial) apoptotic pathway through the proapoptotic protein BIM and its phosphorylated form (P-BIM). PTPN2 modulates β-cell death induced by interferons by regulating activation of P-BIM via JNK1. BIM and/or JNK1 are downregulated by BACH2, GLIS3 and CTSH. PTPN2 also functions as a negative regulator of the STAT signalling pathway, whereas USP18 exerts negative feedback on interferon-induced STAT signalling and mitochondrial apoptotic pathways in β cells. Candidate-gene regulated factors implicated in type 1 diabetes mellitus are framed in red and the consequences of their modulated expression and/or activity on biological function or type 1 diabetes mellitus risk indicated. Kinases and phosphatases are indicated by green ovals and transcription factors by grey ovals.

Figure 2. Crosstalk between viral infection, genetic background and early education of the immune system

Genetic background and early immune education, either alone or in combination, define the individual's capacity to modulate the cell autonomous response upon viral infection. These diverse responses to viral infection can lead to different outcomes, including excessive β-cell loss (with or without viral persistence) and triggering of an autoimmune response. Repeated viral infection might accelerate the ongoing autoimmune assault against β cells, culminating in clinical disease. AS, alternative splicing; ER, endoplasmic reticulum; T1DM, type 1 diabetes mellitus.

Figure 3. Differential autonomous antiviral response determines the outcome of infection in pancreatic α cells and β cells

a | and b | Viral protein expression in human islet cells infected by coxsackievirus B5 serotype (CVB5) for 8 h. Immunocytochemistry labelling of VP1 (red), insulin (green), glucagon (light blue) and nuclei (dark blue) indicates expression of the viral protein at an early time point of infection in both insulin-producing-β cells (part a) and glucagon-producing-α cells (part b). Scale bar, 1 μm. c | Time course of CVB5 proliferation versus expression of antiviral response genes in rat α cells and β cells. Purified rat α cells and β cells were infected with CVB5 and examined at 1, 2, 4, 6, 8 and 24 h after infection. The mRNA expression levels of antiviral genes (Stat1 and Mx1) and viral genes (VP1) are shown. Basal expression of antiviral genes is higher in α cells than in β cells and rapidly increases, which enables this cell type to eradicate the viral infection and survive. By contrast, β cells exhibit lower and less effective antiviral responses than α cells, which enables the viral load to increase and eventually kill the infected cells.