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Progression to type 1 diabetes and autoantibody positivity in relation to HLA-risk genotypes in children participating in the ABIS study
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
Dept of Microbiology Kuopio, Finland.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
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2008 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 9, no 3 PART 1, 182-190 p.Article in journal (Refereed) Published
Abstract [en]

Background: Autoantibodies against beta-cell antigens together with human leukocyte antigen (HLA)-risk genotypes are used as predictive markers for type 1 diabetes (T1D). In this study, we have investigated the role of HLA-risk and -protective genotypes for development of beta-cell autoantibodies and progression to T1D in healthy children. Methods: T1D-related HLA genotypes and autoantibodies against glutamic acid decarboxylase [glutamic acid decarboxylase antibodies (GADA)] and islet antigen-2 (IA-2A) were studied at 1, 2.5 and 5 yr of age in unselected healthy children and children with T1D participating in the All Babies In Southeast Sweden (ABIS) study. Results: GADA or IA-2A positivity at 5 yr of age was associated with DR4-DQ8 haplotype and DR3-DQ2/DR4-DQ8 genotype. By the age of 6-7 yr, we identified 32 children with T1D among the 17 055 participants in the ABIS study. Eight of 2329 (0.3%) non-diabetic children had permanent autoantibodies, and 143 of 2329 (6%) children had transient autoantibodies. HLA-risk genotypes associated with T1D, whereas protective genotypes were seldom found in children with T1D. Children with permanent autoantibodies had more often risk-associated DR4-DQ8 haplotype than autoantibody-negative children. No associations with HLA-risk or -protective genotypes were found for transient autoantibodies. Conclusions: The strong relation between HLA-risk alleles and T1D once again confirmed that HLA-risk genotypes play an important role for development of T1D. However, HLA genotypes seem not to explain induction of autoantibodies, especially transient autoantibodies, in the general population, emphasizing the role of environmental factors in the initiation of autoimmunity. It seems that HLA-risk genotypes are responsible for maturation of the permanent autoantibody response. © 2008 The Authors Journal compilation © 2008 Blackwell Munksgaard.

Place, publisher, year, edition, pages
2008. Vol. 9, no 3 PART 1, 182-190 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-42864DOI: 10.1111/j.1399-5448.2008.00369.xLocal ID: 69621OAI: diva2:263721
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-02-14
In thesis
1. Autoantibodies related to type 1 diabetes in children
Open this publication in new window or tab >>Autoantibodies related to type 1 diabetes in children
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is an autoimmune disease resulting from destruction of the insulin producing beta cells in the pancreas. The patients need life-long heavy treatment and still complications, both acute and later in life, are common. The incidence of type 1 diabetes has increased rapidly during the last decades, especially among young children. The disease can be predicted by genes predisposing type 1 diabetes, mainly human leukocyte antigen (HLA) genes, together with presence of autoantibodies to beta-cell antigens, where multiple autoantibodies confer the highest risk. A number of immune system intervention trials are now ongoing aiming to halt the progression of the inflammatory process in the beta cells.

This thesis aimed to investigate the prevalence and levels of autoantibodies in healthy children and in children with type 1 diabetes. Another aim was to study different properties of one of these autoantibodies, such as to which epitopes the antibodies bind and the distribution of immunoglobulin (Ig)-G subclasses, after immunomodulatory treatment in children with type 1 diabetes.

We found that positivity to autoantibodies against glutamic acid decarboxylase (GADA) and tyrosine phosphatase like protein islet antigen-2 (IA-2A) was associated with HLA risk genotypes in 5-year old children from the general population. HLA risk genotypes seemed important for persistence of autoantibodies and for development of type 1 diabetes, while emergence of autoantibodies, especially transient autoantibodies, seemed to be more influenced by environmental factors. Improved methods for detection of autoantibodies are needed, for prediction of diabetes and for identification of high-risk individuals suitable for prevention treatments. Therefore, an assay for measurement of insulin autoantibodies (IAA), based on surface plasmon resonance (SPR), was developed. The main advantages of this method are that there is no need for labelling and that it is time-saving compared to the traditionally used radioimmunoassay (RIA), but further development of the method is needed.

Treatment with GAD-alum (Diamyd) in children with type 1 diabetes has shown to preserve residual insulin secretion. This clinical effect was accompanied by an increase in GADA levels. We investigated the epitope reactivity of GADA in both GAD-alum and placebo treated children, and found that binding to one of the tested epitopes was temporarily increased after injection of GAD-alum. This result suggests that the quality of GADA was, to some extent, transiently affected by the treatment. On the other hand, no changes in binding to epitopes associated with stiff person syndrome (SPS) were observed, which together with the lack of change in GAD65 enzyme activity further strengthens the safety of the treatment. We also observed that the distribution of IgG subclasses was changed by GAD-alum treatment, with a lower proportion of IgG1 and higher IgG3 and IgG4. Lower IgG1 and higher IgG4 suggest a temporary switch towards a protective Th2 immune response, which has previously been observed in the same individuals for other immunological markers.

In conclusion, measurement of autoantibodies related to type 1 diabetes is an important tool for studying the autoimmune process in pre-diabetic and type 1 diabetic children. In addition to the use as markers of disease progression, the autoantibodies may be used for studying the effects of immunomodulatory treatments on the humoral immune response.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 116 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1218
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-64593 (URN)978-91-7393-276-9 (ISBN)
Public defence
2011-02-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2011-01-28 Created: 2011-01-28 Last updated: 2015-06-05Bibliographically approved

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Gullstrand, CamillaWahlberg Topp, JeanetteVaarala, OutiLudvigsson, Johnny
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PediatricsFaculty of Health SciencesInternal MedicineDepartment of Endocrinology and Gastroenterology UHLDepartment of Paediatrics in Linköping
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Pediatric Diabetes
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