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Aberrancies associated with dendritic cells and T lymphocytes in type 1 diabetes
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-30280Local ID: 15797ISBN: 91-85299-28-6 (print)OAI: oai:DiVA.org:liu-30280DiVA: diva2:251102
Public defence
2005-11-25, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-02Bibliographically approved
List of papers
1. Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes
Open this publication in new window or tab >>Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes
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2004 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, no 6, 647-652 p.Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) has been associated with an aberrant maturation of dendritic cells (DC). We studied the maturation of monocyte-derived DC in children with newly diagnosed T1D and in healthy children with genetic risk for T1D. Peripheral blood monocytes from children with newly diagnosed T1D (n = 12; mean age 13.2 years), children with human leukocyte antigen (HLA)-risk genotype of T1D (n = 7; mean age 12.7 years) and healthy children (n = 14; mean age 11.2 years) were in vitro differentiated into DC. Expression of HLA-DR, CD80/86 and CD11c and secretion of interleukin (IL)-12, tumor necrosis factor (TNF)-α, IL-6 and IL-10 were measured using flow cytometry. Lower percentage of DC expressed CD11c and HLA-DR, and decreased production of TNF-α was found in children with newly diagnosed T1D and in children at genetic risk when compared to healthy children. Children with risk genotype also had decreased IL-12 production by DC. Children with T1D and children at genetic risk of T1D appear to have similar aberrancies in the maturation of DC, which may predispose to β-cell autoimmunity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22840 (URN)10.1111/j.0300-9475.2004.01521.x (DOI)2178 (Local ID)2178 (Archive number)2178 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-02Bibliographically approved
2. Aberrant regulation of interleukin-12 receptor β2 chain on type 1 cytokine-stimulated T lymphocytes in type 1 diabetes
Open this publication in new window or tab >>Aberrant regulation of interleukin-12 receptor β2 chain on type 1 cytokine-stimulated T lymphocytes in type 1 diabetes
2005 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 114, no 2, 287-293 p.Article in journal (Refereed) Published
Abstract [en]

An aberrant mitogen-induced polarization of peripheral blood T cells has been associated with type 1 diabetes (T1D). We studied, in T1D, type 1 and 2 cytokine-induced expression of the interleukin-12 receptor β2 chain (IL-12Rβ2 chain), which plays a critical role in regulating T-cell polarization. Peripheral blood lymphocytes from children with newly diagnosed T1D (n = 10; mean age 10 years), from children with longstanding T1D (n = 8; mean age 12·9 years) and from healthy children (n = 15; mean age 11·5 years) were stimulated with phytohaemagglutinin (PHA) in a type 1 (IL-12 and anti-IL-4) or a type 2 (IL-4 and anti-IL-12) cytokine environment. Secretion of interferon-γ (IFN-γ), IL-5 and IL-13, as detected by enzyme-linked immunosorbent assay (ELISA), and expression of the IL-12Rβ2 chain on CD4 and CD8 cells by flow cytometry, were analysed. Children with newly diagnosed and longstanding T1D had lower expression levels of the IL-12Rβ2 chain on IL-12Rβ2 chain-positive CD4 T cells (for a type 1 or a type 2 cytokine environment: P = 0·01 and P = 0·002 or P = 0·02 and P = 0·01, respectively) and on IL-12Rβ2 chain-positive CD8 T cells (for a type 1 or a type 2 cytokine environment: P = 0·007 and P = 0·0007 or P = 0·003 and P = 0·01, respectively) when compared to healthy children. A decreased percentage of IL-12Rβ2 chain-expressing CD4 T cells (P = 0·07 and P = 0·03) and CD8 T cells (P = 0·004 and P = 0·01) and increased secretion of IL-13 (P = 0·006 and P = 0·04) in a type 1 cytokine environment was seen in both groups of patients. Peripheral blood T cells from patients with both newly diagnosed and longstanding T1D showed poor polarization towards type 1 cells.

Keyword
IL-12R, IL-13, T cells, type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24403 (URN)10.1111/j.1365-2567.2004.02102.x (DOI)6500 (Local ID)6500 (Archive number)6500 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-02Bibliographically approved
3. Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetes
Open this publication in new window or tab >>Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetes
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In type 1 diabetes the T cell polarization and expression of chemokine receptors have been reported to be aberrant. We asked whether these aberrancies are present already at birth in neonates carrying HLA risk haplotypes for type 1 diabetes.

Cord blood (CB) samples were obtained from neonates taking part in the Trial to Reduce IDDM in Genetically at Risk (TRIGR) and the Finnish Dietary Intervention Trial for Prevention of Type 1 Diabetes (FINDIA) studies and were screened for type 1 diabetes-associated HLA risk genotypes (HLA DR3-DQ2 and/or DR4-DQ8 without protective alleles). CB lymphocytes were stimulated with phytohemagglutinin (PHA) in type 1 (IL-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine- and cytokine receptors on T cells was determined by flow cytometry, cytokines were analyzed with ELISA, and transcription factors were analyzed using real-time RT-PCR.

When compared to the control group, neonates carrying alleles DQ2/DQ8 or DQ8 showed reduced percentage of CD4 T cells expressing CCR4 and lower levels of CCR4 mRNA after culture of CB lymphocytes in type 2 cytokine environment. In addition, these neonates had significantly lower secretion of iL-13 and expression of GATA-3 after culture of CB lymphocytes in type 2 cytok:ine environment in comparison to neonates with no increased genetic risk of type 1 diabetes.

These results suggest aberrancies in the in vitro regulation of type 2 immune responses in children with increased genetic risk of type 1 diabetes when compared to neonates without HLA risk haplotypes suggesting that the HLA genotype may affect the T cell polarization already at birth. Aberrant induction ofT cell polarization may contribute to development of autoimmunity later in life.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-83498 (URN)
Available from: 2012-10-02 Created: 2012-10-02 Last updated: 2012-10-02Bibliographically approved
4. Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes
Open this publication in new window or tab >>Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-34899 (URN)10.2337/diabetes.55.04.06.db05-0630 (DOI)16567521 (PubMedID)23891 (Local ID)23891 (Archive number)23891 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-09-01Bibliographically approved

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