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Effect of HLA genotype or CTLA-4 polymorphism on cytokine response in healthy children
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
University of Kuopio.
National Public Health Institute, Helsinki, Finland .
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
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2008 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, Vol. 68, no 3, 345-350 p.Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) is considered to be a T-cell-mediated autoimmune disease in which genetic predisposition is affected by HLA class II alleles and polymorphisms in cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene. We tested the hypothesis whether these T1D-related gene polymorphisms modulate cytokine response and thus contribute to the development of autoimmunity. The study includes 67 non-diabetic children, typed for HLA class II alleles and CTLA-4 polymorphisms (+49A/G, CT60A/G, CTBC217_1C/T). We measured cytokine secretion of peripheral blood mononuclear cells after stimulation with tetanus toxoid (TT), polio virus, coxsackie virus B4, pertussis toxin (PT) and phytohemagglutinin (PHA). We saw higher IL-13 response to TT in individuals with DR3–DQ2 haplotype (P = 0.002). HLA class II protective haplotype, DR2–DQ6, showed association with increased production of IFN-γ (P < 0.001) and IL-2 (P = 0.005) in response to polio virus. In children with the autoimmunity-related homozygous genotypes CTLA-4 +49G/G, CT60G/G and CTBC217_1T/T, we found enhanced PT- and PHA-induced IFN-γ production (P < 0.05). The cytokine responses to studied antigens were weakly modified by HLA class II risk haplotypes, and children with T1D-associated HLA risk haplotypes are not specifically inclined to develop an immune response in general. Higher IFN-γ and IL-2 response to enterovirus in children with HLA class II protective haplotype DR2-DQ6 could be of importance in the protection from T1D-associated enterovirus infections. All autoimmunity related CTLA-4 polymorphisms were associated with enhanced IFN-γ. This suggests impaired downregulation of cellular immunity by these CTLA-4 polymorphisms.

Place, publisher, year, edition, pages
2008. Vol. 68, no 3, 345-350 p.
National Category
URN: urn:nbn:se:liu:diva-12436DOI: 10.1111/j.1365-3083.2008.02144.xOAI: diva2:75
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2009-08-21Bibliographically 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

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Walldén (Fredriksson), JennyLudvigsson, Johnny
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Pediatrics Faculty of Health SciencesDepartment of Paediatrics in Linköping
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