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Ongoing Pathogenic Processes in the Pancreas at Onset of Type 1 Diabetes in Humans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-172584OAI: oai:DiVA.org:uu-172584DiVA: diva2:515075
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2014-01-07
In thesis
1. Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans
Open this publication in new window or tab >>Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on enteroviral effects on human pancreatic islets. Most knowledge of viral effects on host cells relies on studies of immortalized cell lines or animal models. The islets represent a fundamentally different and less well studied cellular host. Also, enterovirus has been implicated in the etiology of type 1 diabetes (T1D). We show that when enterovirus replicates in human islets it activates innate immunity genes and induces secretion of the chemokines MCP-1 and IP-10. An important difference in activation of innate immunity by replicating EV and synthetic dsRNA is suggested, since the chemokine secretion induced by EV infection but not by dsRNA is reduced by female sex hormone. We also demonstrate a direct antiviral effect of nicotinamide, and even though this substance failed to prevent T1D in a large-scale study, this finding could have implications for the treatment/prevention of virus- and/or immune-mediated disease.

We also had access to human pancreata from two organ donors with recent onset T1D and several donors with T1D-related autoantibodies, which gave us the opportunity to study ongoing pathogenic processes at and before the onset of T1D. Despite this, we could neither confirm nor reject the hypothesis that EV is involved in T1D development. Several observations, such as ultrastructural remodeling of the beta cell, activation of innate immunity, and immunopositivity to EV capsid protein 1, supported an ongoing virus infection, but direct evidence is still lacking.

An interesting finding in the donors with recent onset T1D was that the islets were positively stained for insulin, but did not secrete insulin in response to glucose-stimulation. A similar effect was observed in EV-infected islets in vitro; EV destroyed islet function and insulin gene expression, but the islets still stained positive for insulin. This may be indicative of that a functional block in addition to beta cell destruction is involved in T1D pathogenesis.

In conclusion, these studies of EV in isolated human islets in vitro support that this virus can cause T1D in vivo, but future studies will have to show if and how frequently this happens. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 766
Keyword
Type 1 diabetes, Enterovirus, Coxsackievirus, Innate immunity, Pancreatic islets, Islet function
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-172586 (URN)978-91-554-8350-0 (ISBN)
Public defence
2012-05-30, Fåhreussalen, Rudbecklaboratoriet, Dag Hammarskjölds V. 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-09 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved
2. Enterovirus Implications in Type 1 Diabetes
Open this publication in new window or tab >>Enterovirus Implications in Type 1 Diabetes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human enteroviruses (HEVs), particularly Coxsackie B viruses (CVBs), might trigger the onset of type 1 diabetes (T1D), either by direct infection of the insulin-producing beta-cells or by an indirect inflammatory response. The overall aim of this thesis was to study the tropism of HEVs in isolated human pancreatic cell clusters in vitro including virus effects on islet function, gene-expression and ultrastructure. Furthermore, the expression of the major CVB-receptor, CAR, was investigated in pancreatic tissue from T1D-related subjects and CVB-infected islets. Also, tissues and isolated islets from two adult organ-donors who died close to disease onset were studied.The results showed that beta-cells were destroyed through lytic infections with different strains of CVBs and that islets function did not depend on replication per se but on the degree of islet destruction. Virus particles were observed in beta-cells in association with insulin granules, however no virus replication or particles could be observed in the exocrine cell clusters, as opposed to in mice models. The virus-infected islets had a decreased expression of insulin mRNA and CAR mRNA/protein, possibly reflecting virus-killed beta-cells. Infected beta-cells contained a high number of insulin granules, which might indicate an impaired function.The in vivo studies showed presence of virus proteins in the islets of both donors who died close to onset of T1D and elevated expression of innate immunity genes, potentially indicating viral infection, but direct evidence is lacking. Both donors were immune-reactive for insulin but the isolated islets had an impaired or completely lacking glucose response. Ultrastructural analysis showed both damaged beta-cells and normal-looking beta-cells, indicating that the latter might still have the potential to function but were blocked. CAR-expression was significantly increased in T1D-related subjects which might indicate tissue damage and/or inflammation in these subjects.To conclude, these results showed that CVBs could infect human primary beta-cells, likely by binding to CAR and lead to functional abnormalities, indicating that they could cause T1D in vivo. Exocrine cells were not permissive to CVB, which raises the question if mice-models should be used to study human pancreatitis. Also, unique materials from two T1D organ-donors were described.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 918
Keyword
Enterovirus, Coxsackie B virus, Type 1 diabetes, Pancreatitis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204378 (URN)978-91-554-8709-6 (ISBN)
Public defence
2013-09-13, Rudbecklaboratoriet stora aulan, Dag Hammarskjöldsv 20, Uppsala, 09:15 (English)
Supervisors
Available from: 2013-08-30 Created: 2013-08-01 Last updated: 2014-01-07

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