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Autoantibodies as markers of beta-cell autoimmunity in children
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is a chronic disease caused by destruction of the insulin producing beta-cells in the pancreas. The incidence of T1D has increased rapidly, especially in the Western world and among young children. The pathogenesis of T1D is not fully understood, but the beta-cells are believed to be destroyed by an autoimmune process initiated years before the onset of T1D. During this pre-clinical

period, autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the tyrosine phosphatase-like protein IA-2 (IA-2A) can be detected and are used to identify individuals at risk of T1D. The major genetic determinant for T1D is the HLA class II genes, but also polymorphism in the insulin gene and CTLA-4 gene are associated with T1D. The risk genes cannot explain the rapid increase in incidence of T1D, therefore a role for different environmental factors has been suggested.

The aim was to study the prevalence of beta-cell autoantibodies in children from the general population in relation to known genetic and environmental risk factors, and in young patients with T1D in high and low incidence areas.

Short duration of breast-feeding was associated with an increased risk of developing beta-cell autoantibodies in children from the general population at 5-6 years of age. We found an association between positivity for GADA and/or IAA at the age of 5-6 years and a short duration of total breastfeeding, and also between positivity for GADA, IA-2A and/or IAA and a short duration of exclusive breast-feeding. Our findings suggest that breast-feeding has a long term protective effect on the risk of beta-cell autoimmunity in children from the general population. The T1D related risk genes were not associated with beta-cell autoantibodies other than GADA in children from the general population at 5-6 years of age. Children with the DR4-DQ8 haplotype were more often positive for GADA than children without this haplotype. We found no association of GADA with DR3-DQ2 haplotype or between these two haplotypes and any of the other autoantibodies. Our results suggest that beta-cell autoimmunity in children from the general population is not strongly associated with any risk genes of T1D other than DR4-DQ8. In the non-diabetic children with allergic heredity GADA was detectable in almost all children, IA-2A in about half and IAA in 10% of the children. The levels low of these autoantibodies fluctuated with age and different patterns of fluctuations were seen for GADA and IA-2A, which may reflect differences in the immune response to the autoantigens. In patients with newly diagnosed T1D, we found some differences between patients from a high incidence country (Sweden) and a country with a lower incidence (Lithuania). Among the Swedish patients, the prevalence of IAA and GADA or multiple autoantibodies was higher than in Lithuanian patients. The risk genes DR4-DQ8 and the heterozygous high risk combination DR4-DQ8/DR3-DQ2 was more common among the Swedish patients than Lithuanian patients. Patients with low levels of IAA had higher levels of HbA1c and ketones, indicating that patients without IAA or with low levels of IAA have a more severe onset of T1D. Our findings indicate that beta-cell autoimmunity is more pronounced in a high incidence area compared to an area with a lower incidence.

In conclusion, short duration of breast-feeding is a risk factor for beta-cell autoantibodies in children from the general population, and the beta-cell autoantibodies in these children are not associated with specific risk genes. Children with newly diagnosed T1D in a high incidence area carry risk genes and have autoantibodies more often than newly diagnosed children from an area with a lower incidence, perhaps indicating different disease phenotypes.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin , 2006.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 936
Keyword [en]
Type 1 diabetes, Autoantibodies, Beta-cell autoimmunity, Children, Breast-feeding, HLA haplotypes, Insulin gene
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:liu:diva-7092ISBN: 91-85497-72-X (print)OAI: oai:DiVA.org:liu-7092DiVA: diva2:22156
Public defence
2006-03-10, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2006-07-11 Created: 2006-07-11 Last updated: 2009-08-22
List of papers
1. Induction of diabetes-related autoantibodies below cutoff for "positivity" in young nondiabetic children
Open this publication in new window or tab >>Induction of diabetes-related autoantibodies below cutoff for "positivity" in young nondiabetic children
2003 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 1005, 269-274 p.Article in journal (Refereed) Published
Abstract [en]

The aim was to study the natural course of diabetes-related autoantibodies at low concentrations, below "positivity", in a nondiabetic population followed up from infancy. Blood samples were taken from 205 children at 6 weeks, 6 months, 18 months, and 5 years of age. Autoantibodies against GAD65 (GADA), tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by radioligand-binding assays. All children had detectable levels of GADA and approximately half had IA-2A, but only approximately 10% had detectable levels of IAA during the follow-up period. Many children developed IA-2A already at 6 months of age, similar concentrations were seen at 18 months, and then the levels of IA-2A decreased until 5 years of age. GADA were induced less often at 6 months of age, increased up to 18 months, and fluctuated at similar levels up to 5 years of age. IAA were detectable in so few children and at low levels, so no trend in natural course could be revealed. We conclude that there is a natural induction of humoral immune response to β cell autoantigens early in life. Our results suggest that the mechanisms of β cell tolerance to GAD and IA-2 differ in healthy children.

Keyword
IA-2, GAD, insulin, healthy children, tolerance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13896 (URN)10.1196/annals.1288.041 (DOI)
Available from: 2006-07-11 Created: 2006-07-11 Last updated: 2009-08-18
2. Higher prevalence of autoantibodies to insulin and GAD65 in Swedish compared to Lithuanian children with type 1 diabetes
Open this publication in new window or tab >>Higher prevalence of autoantibodies to insulin and GAD65 in Swedish compared to Lithuanian children with type 1 diabetes
Show others...
2006 (English)In: Diabetes Research & Clinical Practice, ISSN 0168-8227, Vol. 72, no 3, 308-314 p.Article in journal (Refereed) Published
Abstract [en]

We compared the prevalence of beta-cell autoantibodies and genetic risk factors in Sweden and Lithuania. Ninety-six patients from Sweden and 96 from Lithuania matched for age and gender (1–15 years old, median age 9.0 years) were included. We analyzed autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase like IA-2 (IA-2A) as well as risk-associated polymorphisms of HLA, insulin and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) genes.

The frequency of patients positive for IAA and GADA was higher in Sweden than in Lithuania (p=0.043 and 0.032). The differences remained even when the patients were matched for HLA, insulin and CTLA-4 risk genotypes. Patients with low levels of IAA had higher levels of HbA1c and ketones at diagnosis. The frequency of the risk haplotype DR4-DQ8 was higher in Swedish than in Lithuanian patients (p=0.004), as well as the high-risk combination of DR4-DQ8 and DR3-DQ2 haplotypes (p=0.009).

Our results suggest that autoimmune process against insulin and GAD65 is more common at diagnosis in children in areas with high incidence of type 1 diabetes (T1D), independent of genetic risk markers. Furthermore, the disease in patients with insulin autoantibodies seems to be clinically milder.

Keyword
Beta-cell autoantibodies, Type 1 diabetes, Sweden, Lithuania, HLA risk genotype
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13897 (URN)10.1016/j.diabres.2005.10.022 (DOI)
Available from: 2006-07-11 Created: 2006-07-11
3. Short duration of breast-feeding as a risk-factor for β-cell autoantibodies in 5-year-old children from the general population
Open this publication in new window or tab >>Short duration of breast-feeding as a risk-factor for β-cell autoantibodies in 5-year-old children from the general population
2007 (English)In: British Journal of Nutrition, ISSN 0007-1145, Vol. 97, no 1, 111-116 p.Article in journal (Refereed) Published
Abstract [en]

Breast-feeding has been suggested to have a protective effect against the development of type 1 diabetes. In the present study, we investigated the relation between duration of breast-feeding and β-cell autoantibodies in 5-year-old non-diabetic children who participated in a prospective population-based follow-up study (the All Babies in Southeast Sweden study). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase-like IA-2 (IA-2A) were measured by radiobinding assays. A short duration of total breast-feeding was associated with an increased risk of GADA and/or IAA above the ninety-fifth percentile at 5 years of age (OR 2-09, 95% CI 1-45, 3-02; P<0-000) as well as with an increased risk of IAA above the ninety-fifth percentile at this age (OR 2-89, 95% CI 1-81, 4-62; P<0-000). A short duration of exclusive breast-feeding was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 2-01, 95% CI 1-08, 3-73; P = 0-028) as well as with an increased risk of IA-2A above the ninety-ninth percentile (OR 3-50, 95% CI 1-38, 8-92; P = 0-009) at 5 years of age. An early introduction of formula was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 1-84, 95% CI 1-01, 3-37; P = 0-047) at 5 years of age. The positive association between a short duration of both total and exclusive breast-feeding, as well as an early introduction of formula, and positivity for β-cell autoantibodies in children from the general population suggests that breast-feeding modifies the risk of β-cell autoimmunity, even years after finishing breast-feeding.

Keyword
Breast-feeding, b-cell autoantibodies, Children, General population
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13898 (URN)10.1017/S0007114507210189 (DOI)
Available from: 2006-07-11 Created: 2006-07-11 Last updated: 2009-04-30
4. HLA haplotypes and insulin gene VNTR polymorphism in relation to markers of beta-cell autoimmunity in children from the general population
Open this publication in new window or tab >>HLA haplotypes and insulin gene VNTR polymorphism in relation to markers of beta-cell autoimmunity in children from the general population
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-13899 (URN)
Available from: 2006-07-11 Created: 2006-07-11 Last updated: 2010-01-13

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