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Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Laboratory for Immunobiology, Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland .
Enterovirus Laboratory, Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland .
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2006 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 4, 996-1003 p.Article in journal (Refereed) Published
Abstract [en]

Enteroviruses, particularly Coxsackie virus B4 (CVB4), are considered to be involved in the pathogenesis of type 1 diabetes. We wanted to compare the characteristics of T-cell immune response to CVB4 in children with type 1 diabetes and healthy children with and without HLA risk-associated haplotypes (HLA-DR3-DQ2 or HLA-DR4-DQ8) for type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with CVB4 and analyzed for cytokine and chemokine receptors by flow cytometry and for expression of transcription factors Tbet and GATA-3 by RT-PCR and Western blot. Culture supernatants were analyzed for secretion of γ-interferon (IFN-γ). In children with type 1 diabetes, a decreased percentage of T-cells expressed CCR2, CXCR6, interleukin (IL)-18R, and IL-12Rβ2-chain after in vitro stimulation with CVB4 in comparison with healthy children with or without HLA risk genotype. Moreover, we found that children with type 1 diabetes had decreased IFN-γ secretion and expression of Tbet, both on mRNA and protein level, in CVB4-stimulated PBMCs. Accordingly, children with type 1 diabetes show an impaired type 1 immune response against CVB4 compared with healthy children. This may lead to a delayed clearance of the virus and, at least partly, explain why children with type 1 diabetes may be more prone to CVB4 infections and related complications, such as β-cell damage.

Place, publisher, year, edition, pages
American Diabetes Association , 2006. Vol. 55, no 4, 996-1003 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-34899DOI: 10.2337/diabetes.55.04.06.db05-0630PubMedID: 16567521Local ID: 23891OAI: oai:DiVA.org:liu-34899DiVA: diva2:255747
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Aberrancies associated with dendritic cells and T lymphocytes in type 1 diabetes
Open this publication in new window or tab >>Aberrancies associated with dendritic cells and T lymphocytes in type 1 diabetes
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The incidence of type 1 diabetes has rapidly increased in the Western world and the age of onset has shifted to younger ages. Type 1 diabetes is a chronic disease caused by destruction of the insulin producing ß-cells in the pancreas leading to severe insulin deficiency. This results in hyperglycaemia and diagnosis of overt type 1 diabetes.

The pathogenesis of type 1 diabetes is not fully understood. When diagnosed during childhood, the ß-cell destruction is believed to be caused by autoreactive T cells in the majority of cases. The effect of autoreactive T cells is limited by dendritic cells, which are involved in the induction of tolerance and in regulating T cells. Different subsets of T cells also play a role in regulating immune responses. The activation of autoreactive T cells is believed to be triggered by environmental factors e.g. coxsackievirus B4 and/or dietary factors. The major genetic determinant for type 1 diabetes is associated with the HLA class II genes encoding the HLA molecules on antigen presenting cells.

The aim of the present study was to study the maturation of dendritic cells and how T cell reactivity is influenced by genetic and environmental factors in children with type 1 diabetes and/or children with increased genetic risk of developing type 1 diabetes in comparison to healthy children.

The maturation of dendritic cells was studied by in vitro differentiation of monocytes into dendritic cells. Our results showed that children with type 1 diabetes and those with genetic risk of type 1 diabetes had a lower percentage of dendritic cells expressing CD11c and HLA-DR in addition to decreased secretion of TNF.

The regulation of T cell polarization was investigated in children with type 1 diabetes and in neonates at genetic risk of type 1 diabetes by in vitro polarization of T cells. Children with newly diagnosed and longstanding type 1 diabetes had a lower number of CD4 and CD8 T cells expressing IL-12Rß2-chain and increased secretion of IL-13 from lymphocytes cultured in type 1 cytokine environment in comparison to healthy children. Neonates carrying type 1 diabetes risk associated haplotypes DQ2/DQ8 or DQ8 had a lower percentage of CD4 T cells expressing CCR4, lower mRNA levels of CCR4 and GATA-3 and lower secretion of IL-13 in lymphocytes cultured in type 2 cytokine environment compared to neonates without genetic risk of type 1 diabetes. Furthermore, we found that children with type 1 diabetes had a lower percentage of CD4 and CD8 T cells expressing CCR2, CXCR6 and IL-18R after in vitro stimulation of peripheral blood mononuclear cells with coxsackievirus B4 in comparison to healthy children with and without genetic risk of type 1 diabetes. We also found decreased secretion of IFN-γ and lower levels of Tbet mRNA from peripheral blood mononuclear cells stimulated with coxsackievirus B4 in children with type 1 diabetes compared to healthy children with and without genetic risk of type 1 diabetes.

In conclusion, defects in the function of dendritic cells and in the polarization of T cells may contribute to an underlying immunological environment, which allows autoimmune responses to develop and impair the host defence mechanisms against pathogens. Ultimately these immunological aberrancies may lead to development of ß-cell autoimmunity.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 122 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 920
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-30280 (URN)15797 (Local ID)91-85299-28-6 (ISBN)15797 (Archive number)15797 (OAI)
Public defence
2005-11-25, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
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Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-02Bibliographically approved

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Skarsvik, SusannePuranen, JuliaHolmberg, HannaLudvigsson, JohnnyVaarala, Outi

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