liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
No evidence for activation of TH1 or TH17 pathways in unstimulated peripheral blood mononuclear cells from children with ß-cell autoimmunity or T1D
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
National Public Health Institute, Helsinki, Finland.
University of Kuopio and Laboratory, University of Turku, Finland.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Show others and affiliations
2008 (English)In: Journal of Inflammation Research, ISSN 1178-7031, Vol. 1, 11-17 p.Article in journal (Refereed) Published
Abstract [en]


The balance between T(H)1, T(H)2, T(H)17, and regulatory T cells has been suggested to be disturbed in type 1 diabetes (T1D). We investigated this balance in peripheral blood mononuclear cells (PBMC) from children at risk of developing T1D and children with T1D.


We studied PBMC expression levels of markers related to T(H)1 (T-bet, IL-12Rβ(1), IL-12Rβ(2)), T(H)2 (GATA-3, IL-4Rα), T(H)17 (IL-17A), and regulatory T cells (Foxp3, ICOS, and CTLA-4) with real-time polymerase chain reaction from 17 children with T1D, 13 children with β-cell autoimmunity, 15 children with T1D risk-associated human leukocyte antigen (HLA) haplotypes, and 24 healthy, control children.


We observed decreased expression levels of GATA-3 by PBMC of healthy children with autoantibodies compared to healthy, control children (p = 0.014) or children with HLA risk alleles (p = 0.032). Children with T1D demonstrated lower expression levels of T-bet, IL-12Rβ(1), and IL-4Rα both at diagnosis and 12 months later.


We found no indication of aberrant activation of T(H)1, T(H)17, or Treg in peripheral blood from children with or without risk of T1D. The observed immunological differences between children at risk of and with T1D should be considered when immunopathogenesis of β-cell destruction is studied.

Place, publisher, year, edition, pages
Dove Medical Press , 2008. Vol. 1, 11-17 p.
Keyword [en]
Transcription factor, type 1 diabetes, mononuclear cells
National Category
URN: urn:nbn:se:liu:diva-12434PubMedID: 22096343OAI: diva2:72
Available from: 2009-03-06 Created: 2008-09-04 Last updated: 2014-09-02Bibliographically 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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1075
National Category
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)
Available from: 2008-09-17 Created: 2008-09-04 Last updated: 2009-08-25Bibliographically approved

Open Access in DiVA

fulltext(494 kB)333 downloads
File information
File name FULLTEXT01.pdfFile size 494 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

PubMedLink to articleLink to Ph.D. Thesis

Search in DiVA

By author/editor
Walldén (Fredriksson), JennyLudvigsson, Johnny
By organisation
PediatricsFaculty of Health Sciences
In the same journal
Journal of Inflammation Research

Search outside of DiVA

GoogleGoogle Scholar
Total: 333 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 246 hits
ReferencesLink to record
Permanent link

Direct link