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Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
Paediatric Department, Oslo University Hospital, Oslo, Norway.
Intervention Centre and Department of Surgery, Oslo University Hospital, Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway.
(Faculty of Medicine, University of Oslo, Oslo, Norway Department of Surgery, Oslo University Hospital, Oslo, Norway)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 5, 1682-1687 p.Article in journal (Refereed) Published
Abstract [en]

The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh frozen whole pancreatic tissue using PCR and sequencing. Non-diabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. Only 1.7 % of the islets contained VP1 positive cells and the amount of enterovirus RNA was low. The results provides evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.

Place, publisher, year, edition, pages
2015. Vol. 64, no 5, 1682-1687 p.
National Category
Endocrinology and Diabetes Microbiology
URN: urn:nbn:se:uu:diva-239513DOI: 10.2337/db14-1370ISI: 000353431200023PubMedID: 25422108OAI: oai:DiVA.org:uu-239513DiVA: diva2:774773
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2016-06-01
In thesis
1. Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells
Open this publication in new window or tab >>Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied.

Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1223
Type 1 Diabetes, Enterovirus, Innate Immunity, Pancreas
National Category
Microbiology in the medical area
urn:nbn:se:uu:diva-284370 (URN)978-91-554-9572-5 (ISBN)
Public defence
2016-06-07, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 752 37 Uppsala, Uppsala, 09:00 (English)
Available from: 2016-05-13 Created: 2016-04-18 Last updated: 2016-06-01

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