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Effects on isolated human pancreatic islet cells after infection with strains of enterovirus isolated at clinical presentation of type 1 diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Tuvemo)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Tuvemo)
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2007 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 124, no 1-2, 193-203 p.Article in journal (Refereed) Published
Abstract [en]

Enterovirus (EV) infections have been associated with the pathogenesis of type 1 diabetes (T1D). They may cause β-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Evidence for EV involvement have been presented in several studies, EV-IgM antibodies have been reported in T1D patients, EV-RNA has been found in the blood from T1D patients at onset, and EV have been isolated from newly diagnosed T1D. Our aim was to study infections with EV isolates from newly diagnosed T1D patients in human pancreatic islets in vitro. Two of them (T1 and T2) originated from a mother and her son diagnosed with T1D on the same day, the other two (A and E) were isolated from a pair of twins at the time of diagnosis of T1D in one of them. Isolated human pancreatic islets were infected and viral replication, viability and degree of cytolysis as well as insulin release in response to high glucose were measured. All four EV isolates replicated in the islet cells and virus particles and virus-induced vesicles were seen in the cytoplasm of the β-cells. The isolates varied in their ability to induce cytolysis and to cause destruction of the islets and infection with two of the isolates (T1 and A) caused more pronounced destruction of the islets. Infection with the isolate from the healthy twin boy (E) was the least cytolytic. The ability to secrete insulin in response to high glucose was reduced in all infected islets as early as 3 days post infection, before any difference in viability was observed. To conclude, strains of EV isolated from T1D patients at clinical presentation of T1D revealed β-cell tropism, and clearly affected the function of the β-cell. In addition, the infection caused a clear increase in the number of dead cells.

Place, publisher, year, edition, pages
2007. Vol. 124, no 1-2, 193-203 p.
Keyword [en]
Enterovirus, β-cells, Type 1 diabetes
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-96817DOI: 10.1016/j.virusres.2006.11.004ISI: 000244924900022PubMedID: 17169456OAI: oai:DiVA.org:uu-96817DiVA: diva2:171520
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2011-02-09Bibliographically approved
In thesis
1. Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
Open this publication in new window or tab >>Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is due to a selective loss of the insulin producing β-cells. However, the process responsible for this loss is still unknown. There is accumulating evidence that enteroviruses (EVs) are involved in T1D. In addition to direct virus-induced cytolysis, EVs could facilitate β-cell destruction by inducing inflammatory cytokines. Induction of such genes has previously been shown in EV-infected islets in vitro. Modulation of inflammatory mediators expressed in the islets could be a possible strategy to reduce β-cell destruction.

In the first paper we screened uninfected isolated human islets for genes with the potential to induce or modulate an immune response. We found that several of the genes expressed in the islets encode proteins with a powerful biological activity, such as IL-1β, IL-8, MIP-2α, MCP-1 and MIF. This indicates that the islets themselves can express several triggers of inflammation, and if expressed in vivo these mediators would probably contribute to β-cell destruction.

The vitamin B3 derivate, nicotinamide (NA), has been shown to modulate expression of factors important for coagulation and inflammatory responses. Addition of NA into isolated islet cultures resulted in a reduced expression of the pro-inflammatory chemokine MCP-1 and the coagulation activator tissue factor, suggesting that NA may have implications for both inflammatory responses and the pro-coagulant activity of islets.

We successfully isolated EVs from three newly diagnosed T1D patients. All isolates showed tropism for human islets and β-cells in vitro and clearly affected islet function. We also found that EV infection induced islet secretion of the chemokines IP-10 and MCP-1and that this induction could be blocked or reduced by addition of NA to the culture medium. Interestingly, NA also reduced viral replication and virus-induced islet destruction.

To conclude, this thesis provides new information about expression and modulation of inflammatory mediators in infected and uninfected human islets that could trigger inflammatory reactions leading to β-cell destruction. Moreover, it further strengthens the causal relationship between EV and T1D.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 316
Immunology, diabetes, islets of Langerhans, enterovirus, inflammatory mediators, cytokines, nicotinamide, Immunologi
urn:nbn:se:uu:diva-8501 (URN)978-91-554-7112-5 (ISBN)
Public defence
2008-04-05, Rudbecksalen, Rudbecklaboratoiet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved

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Elshebani, AsmaOlsson, AnnikaTuvemo, TorstenKorsgren, OlleFrisk, Gun
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