Enteroviruses in the pathogenesis of type 1 diabetes

Abstract

The question if enteroviruses could cause beta-cell damage and type 1 diabetes has become more and more relevant when recent studies have provided new evidence supporting this scenario. One important observation is the recent discovery of IFIH1 as a risk gene for type 1 diabetes. This gene is an innate immune system receptor for enteroviruses offering one possible mechanism for the diabetogenic effect of enteroviruses. This is further emphasized by the observations suggesting that the innate immune system is activated in the pancreatic islets of type 1 diabetic patients and that the innate immune system is important for the defense against the virus and for the regulation of adaptive immune system. Important progress has also been gained in studies analyzing pancreas tissue for possible presence of enteroviruses. Several studies have found enteroviruses in the pancreatic islets of type 1 diabetic patients using various methods. The virus seems to be located in the islets while exocrine pancreas is mostly uninfected. One recent study found the virus in the intestinal mucosa in the majority of diabetic patients. Enteroviruses can also infect cultured human pancreatic islets causing either rapid cell destruction or a persistent-like noncytolytic infection. Combined with all previous, epidemiological findings indicating the risk effect of enteroviruses in cross-sectional and prospective studies, these observations fit to a scenario where certain diabetogenic enterovirus variants establish persistent infection in gut mucosa and in the pancreatic islets. This in turn could lead to a local inflammation and the breakdown of tolerance in genetically susceptible individuals. This is also supported by mouse experiments showing that enteroviruses can establish prolonged infection in the pancreas and intestine, and some virus strains cause beta-cell damage and diabetes. In conclusion, recent studies have strengthened the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes. These findings open also new opportunities to explore the underlying mechanism and get closer to causal relationship.

Experience of a serious life event increases the risk for childhood type 1 diabetes: the ABIS population-based prospective cohort study

“…In relation to other environmental factors discussed as risk factors, the increase in risk found in our study is comparable to that of factors such as birthweight [4], infant nutrition factors [3] and enterovirus infection [2]. However, when comparing single risk factors, heredity is still much more important.…”

“…It is usually preceded by autoimmune destruction of insulin-producing beta cells in genetically predisposed individuals [1], and several environmental factors such as viral infections [2], dietary habits in infancy [3], birthweight and early weight gain [4], as well as chronic stress [5], have been proposed as risk factors. The incidence among young children is increasing in most countries in the world [6], suggesting that environmental factors need to be examined seriously.…”

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

“…The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon. Enteroviruses have been linked to type 1 diabetes in a number of previous studies, as reviewed previously (1,2). The recent discovery of diabetes-associated polymorphisms in the innate immune system receptor for enteroviruses (IFIH1) has further increased the interest in the role of enterovirus infections in the pathogenesis of the disease (3).…”

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

“…In addition, other immune-mediated mechanisms can contribute to the cell damage. Such mechanisms include immunological cross-reactivity between viral and host antigens (molecular mimicry) and possible induction of non-neutralizing anti-viral "enhancing" antibodies, which can lead to strong immune activation and worsen the pathogenesis [7,[18][19][20]. A hypothetical model of some key determinants of EV diabetogenicity is shown in Figure 1.…”