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Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children
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.
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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. Vol. 6, no 4, 199-205 p.
Keyword [en]
Autoantibodies, cow’s milk, gastrointestinal infections, seasonality, T1D
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-12437DOI: 10.1111/j.1399-543X.2005.00129.xOAI: oai:DiVA.org:liu-12437DiVA: diva2:76
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2017-12-05Bibliographically 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
2. Environmental determinants associated with Type 1 diabetes-related autoantibodies in children
Open this publication in new window or tab >>Environmental determinants associated with Type 1 diabetes-related autoantibodies in children
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Type 1 diabetes is a severe disease, which affects children with potentially severe consequences. The global incidence of Type 1 diabetes is increasing rapidly especially in young children. Second to Finland, Sweden has the highest incidence of Type 1 diabetes in the world.

The rapidly increasing incidence cannot be explained by a possible variability of the presence of risk genes in the population, but rather environmental factors.

Therefore, environmental factors contributing to ß-cell auto immunity should be of importance for the process leading up to clinical Type I diabetes in genetically predisposed individuals. Those factors should preferably be revealed early in life. The aim of this thesis was to investigate a large population of Swedish children in order to identify environmental factors, which could contribute to the autoimmune reaction towards insulin-producing ß-cells.

Material and methods

Families from the prospective population-based ABIS-project (All Babies in southeast Sweden) were studied. Blood samples from children were analysed at birth, one year and 2½ years of age for diabetes-related autoantibodies towards Tyrosine phosphatase (IA-2A) and Glutamic Acid Decarboxylase (GAD). The parents completed questionnaires at birth, one year and 2½ years of age.

Results

Short breast-feeding period, early exposure to cow's milk formula and late introduction of gluten-containing foods as well as large consumption of cow's milk at the age of one year were all risk determinants for development of autoantibodies at 2½ years of age. Combined early introduction of cow's milk formula and late introduction of gluten-containing food increased the risk six times for acquiring persistent autoantibodies at 2½ years of age. Parenting stress and experiences of serious life events were associated with the induction of diabetes-related autoimmunity. Infections during pregnancy are related to diabetes-related autoantibodies in cord blood and at the age of one year.

Allergic symptoms such as rash, wheezing, allergy against fur-bearing animals and food allergies implied a risk for development of diabetes-related autoantibodies. Autoantibodies in cord blood had disappeared at the age of one year, and can therefore not be used as a screening method to predict diabetes in the general population.

Conclusions

None of the examined risk factors alone can explain Type 1 diabetes-related autoimmunity; but early nutrition, parental stress and infections can contribute to the development of diabetes-related autoantibodies.

Autoantibodies in cord blood cannot be used to predict later diabetes-related autoimmunity. Different aberrances in the immune system seem to co-exist in certain individuals.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 112 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 922
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-30278 (URN)15795 (Local ID)91-85497-59-2 (ISBN)15795 (Archive number)15795 (OAI)
Public defence
2005-12-02, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-01Bibliographically approved

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Wahlberg, JeanetteFredriksson (Walldén), JennyNikolic, ElisabetVaarala, OutiLudvigsson, Johnny

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