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Regulatory T cells in children with type 1 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
(English)Manuscript (Other academic)
Abstract [en]

Introduction Function and frequency of CD4+CD25high T cells in type 1 diabetes (T1D) patients has been studied in cross-sectional studies. We wanted to investigate the changes in number and function of CD4+CD25high T cells in children with T1D during follow-up.

Material and Method The study includes in total 35 children with T1D and 17 healthy children. The number of CD4+CD25high regulatory T cells and their CTLA-4 expression was analyzed by flow cytometry and the function as the effect of CD4+CD25high T cells on proliferative and cytokine response after mitogen stimulation.

Results We found no differences between healthy and diabetic children in the amount of CD4+CD25highCTLA-4+ regulatory T cells and the numbers did not change during 18 months follow-up. We observed higher median fluorescence intensity of intracellular CTLA-4 on CD4+CD25high T cells in the diabetic children at diagnos compared to healthy children. Proliferation response to PHA was higher in the CD25depleted PBMC than in the whole PBMC population in diabetic and healthy children. Children with T1D showed a higher spontaneous secretion of IL-10 and TGF-β and higher expression of IFN-γ specific mRNA among CD25depleted PBMC than was seen in healthy children.

Conclusion Our data indicate that children with T1D have similar amounts of circulating CD4+CD25high regulatory cells as healthy children. Our data further suggest an increased activity among regulatory T cells in children with T1D.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12439OAI: oai:DiVA.org:liu-12439DiVA: diva2:77
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Studies of immunological risk factors in type 1 diabetes
Open this publication in new window or tab >>Studies of immunological risk factors in type 1 diabetes
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Type 1 diabetes (T1D) is a chronic, autoimmune disease caused by a T cell mediated destruction of ß-cells in pancreas. The development of T1D is determined by a combination of genetic susceptibility genes and environmental factors involved in the pathogenesis of T1D.

This thesis aimed to investigate diverse environmental and immunological risk factors associated with the development of T1D. This was accomplished by comparing autoantibody development, T cell responses and the function of CD4+CD25+ regulatory T cells between healthy children, children at risk of T1D and T1D patients.

Results: Induction of autoantibodies in as young children as one year old, was associated with previously identified environmental risk factors of T1D, such as maternal gastroenteritis during pregnancy and early introduction of cow’s milk. We did not see any general increase in the activity of peripheral blood TH subtypes in children with HLA class II risk haplotypes associated with T1D, nor were HLA class II risk haplotypes associated with any aberrant cytokine production in response to antigenic stimulation of peripheral blood mononuclear cells. However children with a HLA class II protective haplotype showed an increased production of IFN-γ in response to enteroviral stimulation. CTLA-4 polymorphisms connected with a risk of autoimmune disease were associated with enhanced production of IFN-γ.

Healthy children with ß-cell autoantibodies had a lower expression level of GATA-3 compared to health children with HLA risk genotype or children without risk. Instead, children with manifest T1D showed lower expression levels of T-bet, IL-12Rß1 and IL-4Rα.

Both T1D and healthy children showed the same expression of the regulatory markers Foxp3, CTLA-4 and ICOS in peripheral blood mononuclear cells, and the amount of CD4+CD25+ T cells did neither reveal any differences. The regulatory T cells seemed also to be functional in children with T1D, since increased proliferation after depletion of CD4+CD25high cells from PBMC was demonstrated in T1D as well as in healthy children.However, T1D children did have more intracellular CTLA-4 per CD4+CD25high T cell, increased levels of serum C-reactive protein and higher spontaneous expression of IFN-α in CD25depleted PBMC, all which are signs of activation of the immune system. This suggests a normal or enhanced functional activity of regulatory T cells in T1D at diagnosis.

Conclusions: Our findings emphasize that environmental risk factors do have a role in the development of ß-cell autoimmunity. Our results do not support a systemic activation of the immune system in pre-diabetes or T1D, but instead a possible up-regulation of regulatory mechanisms seems to occur after diagnosis of T1D, which probably tries to dampen the autoimmune reaction taking place.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 106 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1075
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-12441 (URN)978-91-7393-824-2 (ISBN)
Public defence
2008-09-27, Berzeliussalen, Hälsouniversitetet, ingång 65, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2008-09-17 Created: 2008-09-04 Last updated: 2009-08-25Bibliographically approved

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Walldén (Fredriksson), JennyLundberg, AnnaLudvigsson, JohnnyVaarala, Outi

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