Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol

Department of Virology, Medical School, University of Tampere, Biokatu 10, FIN-33520, Tampere, Finland.
Seminars in Immunopathology (Impact Factor: 7.75). 01/2011; 33(1):45-55. DOI: 10.1007/s00281-010-0207-y
Source: PubMed


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.

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    • "Accumulating evidence strongly suggests the contribution of enteroviruses , which belong to the picornavirus group, to the elevated risk of diabetes (Tauriainen et al., 2011; Oikarinen et al., 2011; Tanaka et al., 2009). Since resistance to picornavirus infection has been shown to be dependent on innate immunity (Ida-Hosonuma et al., 2005; Takeuchi and Akira, 2009), the molecules regulating innate immune responses are candidates for determining susceptibility to virus-induced diabetes (Kounoue et al., 2008; Nagafuchi et al., 2013). "
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    ABSTRACT: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.
    05/2015; 36(7). DOI:10.1016/j.ebiom.2015.05.004
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    • "ntly observed that the immunogenic CBV1 strain is highly cytolytic in human pancreatic islet cell cultures [ Anagandula et al . , 2013 ] , a phenomenon which may be linked to its ability to induce strong immune activation . Our findings may also have relevance for epidemiological studies evaluating disease associations of different enteroviruses [ Tauriainen et al . , 2011 ] . Since previous studies have been done using methods , which are not Fig . 4 . Single - step growth kinetics of CBV1 strains time course infection of HeLa cells using CBV1 – 10796 , CBV1 – 10802 , and ATCC strains ( circle , square , and x symbols , respectively ) ."
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    ABSTRACT: Enterovirus infections are usually mild but can also cause severe illnesses and play a role in chronic diseases, such as cardiomyopathies and type 1 diabetes. Host response to the invading virus can markedly modulate the course of the infection, and this response varies between individuals due to the polymorphism of immune response genes. However, it is currently not known if virus strains also differ in their ability to stimulate the host immune system. Coxsackievirus B1 (CBV1) causes severe epidemics in young infants and it has recently been connected with type 1 diabetes in seroepidemiological studies. This study evaluated the ability of different field isolates of CBV1 to induce innate immune responses in PBMCs. CBV1 strains differed markedly in their capacity to induce innate immune responses. Out of the 18 tested CBV1 strains two induced exceptionally strong alpha interferon (IFN-α) response in PBMC cultures. The responding cell type was found to be the plasmacytoid dendritic cell. Such a strong innate immune response was accompanied by an up-regulation of several other immune response genes and secretion of cytokines, which modulate inflammation, and adaptive immune responses. These results suggest that enterovirus-induced immune activation depends on the virus strain. It is possible that the immunotype of the virus modulates the course of the infection and plays a role in the pathogenesis of chronic immune-mediated enterovirus diseases. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 08/2014; 86(8). DOI:10.1002/jmv.23903 · 2.35 Impact Factor
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    • "T1D is related to autoimmune process directed against pancreas ␤ cells that produce insulin. The most probable reasons attributed to the emergence of this pathological condition may be listed as: genetic background especially HLA genotype and other genetic loci insulin-dependent diabetes mellitus (IDDM), obesity, diet [1] [2] [3] including action of toxins and food antigens but also other environmental factors [4] like viral infections [5] [6] [7]. Development of T1D could be also considered as immunological response to external stimuli [8]. "
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    ABSTRACT: The aim of this study was to investigate relation between level of HbAc1 and concentration of metabolites in urine of T1D patients. To test this hypothesis the (1)H NMR (proton nuclear magnetic resonance) target analysis of crucial urine metabolites combined with chemometric approach were applied. Urine samples were collected from 30 children and teenagers aged 4-19 with T1D and 12 healthy children, aged 9, as control group. Patients were divided into two groups according to their level of glycated hemoglobin (HbA1c): below (L-T1D) and above 6.5% (H-T1D). The multivariate data analysis (OPLS-DA) was used to explore data and generate the models for selected groups of patients. Two tailed unpaired t-test was used for statistical analysis of quantified metabolites. Comparing to L-T1D patients, H-T1D group exhibited increased levels of alanine, pyruvate and branched amino acid valine that might be related with endogenous glucose production pathway from proteins as well as in the case of T2D. Application of (1)H NMR spectroscopy together with target analysis and chemometric tools based on urine metabolite concentration enable to monitor T1D patients. This methodology can be used as supporting tool for marker HbA1c analysis providing comprehensive information about T1D progression and treatment efficiency.
    Journal of pharmaceutical and biomedical analysis 04/2013; 83C:43-48. DOI:10.1016/j.jpba.2013.04.017 · 2.98 Impact Factor
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