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Studies of immunological risk factors in type 1 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-12441ISBN: 978-91-7393-824-2 (print)OAI: oai:DiVA.org:liu-12441DiVA: diva2:80
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
List of papers
1. Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children
Open this publication in new window or tab >>Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children
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2005 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 6, no 4, 199-205 p.Article in journal (Refereed) Published
Abstract [en]

We studied environmental risk factors which might contribute to the development of beta-cell autoantibodies in healthy children. Here, we investigated 6000 randomly selected children from the large All Babies in Southeast Sweden (ABIS) cohort, including 17 055 newborns recruited between 1997 and 1999. Questionnaires at birth and at 1 yr of age and the levels of autoantibodies to glutamic acid decarboxylase (GADA) and autoantibodies to tyrosine phosphatase (IA-2A) at 1 yr of age were analyzed. The 99th percentile cutoff for autoantibodies was proposed to identify children at risk of type 1 diabetes (T1D) and the 90th percentile cutoff to identify children in whom beta-cell autoimmunity has been induced. Using the 90th percentile cutoff level, 1156 children had either IA-2A (n = 574) or GADA (n = 582), while 126 children had both GADA and IA-2A. When the 99th percentile cutoff level was used, 114 children had either IA-2A (n = 57) or GADA (n = 57), and six children had both GADA and IA-2A. In logistic regression analysis, celiac disease in grandparents [odds ratio (OR) 2.2] and maternal gastrointestinal infection (OR 1.1) represented a risk for simultaneous occurrence of both IA-2A and GADA above the 90th percentile. Birth in spring (March to May) (OR 1.5) and male gender (OR 1.3) were risk factors for induction of IA-2A. Mother's low education represented a risk for induction of IA-2A (OR 1.5) and GADA (OR 1.4). T1D in first-degree relatives increased the risk for beta-cell autoimmunity above the 99th percentile (OR 2.6), whereas type 2 diabetes in grandparents was associated with GADA (OR 2.1). Exposure to cow's milk formulas <2 months of age implied an OR of 2.9 for IA-2A above the 99th percentile.

Place, publisher, year, edition, pages
John Wiley & Sons, 2005
Keyword
Autoantibodies, cow’s milk, gastrointestinal infections, seasonality, T1D
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-12437 (URN)10.1111/j.1399-543X.2005.00129.x (DOI)
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2017-12-05Bibliographically approved
2. No evidence for activation of TH1 or TH17 pathways in unstimulated peripheral blood mononuclear cells from children with ß-cell autoimmunity or T1D
Open this publication in new window or tab >>No evidence for activation of TH1 or TH17 pathways in unstimulated peripheral blood mononuclear cells from children with ß-cell autoimmunity or T1D
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2008 (English)In: Journal of Inflammation Research, ISSN 1178-7031, E-ISSN 1178-7031, Vol. 1, 11-17 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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
Keyword
Transcription factor, type 1 diabetes, mononuclear cells
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-12434 (URN)22096343 (PubMedID)
Available from: 2009-03-06 Created: 2008-09-04 Last updated: 2017-12-05Bibliographically approved
3. Effect of HLA genotype or CTLA-4 polymorphism on cytokine response in healthy children
Open this publication in new window or tab >>Effect of HLA genotype or CTLA-4 polymorphism on cytokine response in healthy children
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2008 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, 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.

National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-12436 (URN)10.1111/j.1365-3083.2008.02144.x (DOI)
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2017-12-05Bibliographically approved
4. Regulatory T cells in children with type 1 diabetes
Open this publication in new window or tab >>Regulatory T cells in children with type 1 diabetes
(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:nbn:se:liu:diva-12439 (URN)
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2010-01-14Bibliographically approved

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