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Diabetes

A virus–gene collaboration

Nature volume 459, pages 518519 (28 May 2009) | Download Citation

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Viral infection has long been implicated in the development of type 1 diabetes. Fresh evidence shows how some rare genetic variations might mediate a viral contribution to this autoimmune disorder.

Type 1 diabetes is an autoimmune disease in which the immune system attacks insulin-producing pancreatic β-cells. As is seen for many other disorders, genome-wide association studies have indicated that variations in certain genomic regions confer susceptibility to this disease, but the precise genes and genetic variants involved remain unknown. The genetic background to type 1 diabetes is complex: some genes protect against the disorder, whereas others promote its development; the two sets act in concert to confer an individual's degree of susceptibility. In addition, environmental factors such as viral infection are thought to contribute to the disease process1. Writing in Science, Nejentsev et al.2 provide genetic evidence further implicating viral infection in the development of type 1 diabetes.

Of the 15 loci in the human genome that have previously been associated with type 1 diabetes, 10 candidate genes were subjected to a detailed analysis by the authors2. Specifically, they used the 454 sequencing technology for high-throughput, detailed sequencing of the genes' exons (coding sequences) and splice sites in 480 patients with type 1 diabetes and 480 healthy controls. They then tested whether the variants identified were associated with the disease in 30,000 patients and controls, including families with one or more children with the disorder.

This extensive analysis led Nejentsev et al. to identify four rare variations, each of which independently lowered the risk of developing type 1 diabetes by about 50%. Intriguingly, all four variants occur in the same gene, IFIH1, affecting the expression and structure of its protein product IFIH1. A helicase enzyme, IFIH1 (also known as MDA5) triggers the secretion of immune mediators known as interferons in response to viral infection. As disabling IFIH1 expression lowers the risk of type 1 diabetes2, this warrants a more detailed look at the role of viral infection as a potential culprit in at least some cases of the disorder.

Viruses, notably human enteroviruses, infect various organs, causing a range of disorders including damage to β-cells. It is unlikely, however, that they commonly cause type 1 diabetes in those with low genetic risk3 and might, instead, contribute to this disorder by infecting β-cells and predisposing them to autoimmune attack. Animal studies have shown that human enteroviruses that replicate fast in vivo cause type 1 diabetes4, whereas those that grow more slowly actually protect against it by activating various regulatory immune mechanisms5.

In the light of Nejentsev and colleagues' results, these observations are relevant to the hitherto rather tenuous link between infections with human enteroviruses and type 1 diabetes. Most, if not all, viral infections trigger the production of interferon by the host immune system (Fig. 1). Being an interferon-response gene, IFIH1 allows the infected cell to sense the RNA genome of enteroviruses and increase interferon production. Interferons then primarily limit viral replication to prevent damage to the infected cell. They also, however, increase the visibility of the infected cell to the immune system by enhancing the expression of surface recognition molecules called major histocompatibility complex (MHC) molecules.

Figure 1: Viral infection, the interferon response and diabetes.
Figure 1

On infection with viruses such as human enteroviruses, interferon-response genes, including IFIH1, are activated in insulin-producing pancreatic β-cells, leading to increased levels of interferon. These immune mediators not only inhibit viral replication, but also enhance the expression of surface MHC-I molecules. Cytotoxic CD8+ T cells recognize infected β-cells through the MHC-I molecules on their surface, damaging and eventually killing them. Thus, viral infection can contribute to the development of type 1 diabetes. In support of this proposal, Nejentsev et al.2 show that rare variations in IFIH1 protect against type 1 diabetes.

What do interferons do to the β-cells? Nothing good, based on animal studies. Together with other inflammatory factors, such as IL-1β and TNF-α, interferons directly contribute to the demise of β-cells6. Moreover, they induce the expression of MHC class I (MHC-I) molecules by these cells. Both effects promote the development of type 1 diabetes in mice7, with enhanced expression of MHC-I proteins perhaps being particularly relevant. Normally, β-cells express low levels of these molecules. Following viral infections, and thus increased interferon production, β-cells express several 100-fold more MHC-I molecules, becoming highly susceptible to recognition and destruction by cytotoxic CD8+ T cells, which recognize both viral and self antigens through MHC-I molecules7. At least in animal models, therefore, unmasking of β-cells to the immune system — associated with viral infection and mediated by interferons — could be an essential step in the development of type 1 diabetes8.

As far as humans are concerned, accumulating evidence also supports a role for viral infection in the development of type 1 diabetes. Indeed, all the main ingredients seem to be present. First, CD8+ T cells are the most common cell type present in human pancreatic islets9, and clones of these cells that can kill human β-cells have been isolated10. Second, and more importantly, several laboratories have reported increased expression of MHC-I molecules (and in some cases, interferons) in pancreatic islets of patients with type 1 diabetes, but not those of controls11. Because many of the islets in these patients had not yet been targeted by the immune system, an underlying viral infection is a plausible explanation for these observations. Indeed, some studies have documented the presence of human enterovirus proteins in islets of patients with type 1 diabetes but not in those of controls12, providing further backing for a role of viruses in the disorder (Fig. 1).

Together with Nejentsev and colleagues' observations, and another study13 showing that IFIH1 expression in peripheral blood cells is associated with type 1 diabetes, these earlier studies point us in a new direction for mechanistic studies of factors contributing to this disorder: virus-mediated interferon production. From an immunogenetic viewpoint, investigations similar to that of Nejentsev et al. should be carried out to define disease-associated variations in genes located within the MHC region, which shows the strongest association with human type 1 diabetes. Detecting structural variations in genes in different individuals will also allow us to devise tailored forms of immunotherapy for specific patient groups with the disorder.

From a virological and immunological standpoint, use should be made of well-preserved, freshly frozen human organ samples, such as those provided by nPOD (the Network for Pancreatic Organ Donors with Diabetes)14, to directly isolate viral sequences, to clone viruses and to rigorously examine islets for the presence of viral footprints such as interferons and increased MHC-I expression. If viral infection proves to be a contributing factor, we could aim to lower the risk of type 1 diabetes by designing suitable vaccines against human enteroviruses.

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  1. Matthias von Herrath is at the La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.  matthias@liai.org

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