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Altered immune profile from pre-diabetes to manifestation of type 1 diabetes
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.
2013 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 1, 74-84 p.Article in journal (Refereed) Published
Abstract [en]

Background: While the mechanisms leading to beta-cell destruction and clinical onset of T1D are still unclear, the composition of the immune profile is probably important for the outcome of immune activity. The aim of this study was to investigate the composition and possible changes of the immunological profile, spontaneously and following stimulation with the autoantigens GAD(65), and HSP60, at high-risk and T1D onset and further to 8 months post diagnosis. Methods: Fifteen first-degree relatives of T1D patients with a high risk of developing the disease within five years, 25 children approximately four days and 8 months after diagnosis of T1D and 16 healthy children were included in the study. Cytokines (IL-1 beta, -6, -7, -10, -13, -17, IFN-gamma and TNF-alpha) and chemokines (CCL2, -3, -4, -5 and CXCL10) associated with Th1, Th2, Tr1 and inflammatory cells were detected in cell culture supernatants by Luminex-technique, and markers associated with regulatory T-cells (FOXP3, CTLA-4 and TGF-beta) by real-time RT-PCR. Results: High-risk individuals differed in immunity from that seen in healthy and T1D children. High-risk individuals had a low TNF-alpha response and fewer responders from mitogen exposure as well as low spontaneous secretions of IL-13 compared to healthy children. High-risk individuals that later developed T1D, had a lower FOXP3 and CTLA-4 mRNA expression, following stimulation with GAD(65), in combination with higher secretion of the pro-inflammatory chemokine CCL4. Conclusion: Changes in immunity seen in individuals with high risk of developing T1D points to alterations/actions in the immune system already early in the pre-diabetic phase.

Place, publisher, year, edition, pages
2013. Vol. 100, no 1, 74-84 p.
Keyword [en]
Type 1 diabetes, pre-diabetes, Th1, Th2, cytokines, chemokines
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71941DOI: 10.1016/j.diabres.2013.01.014ISI: 000317744300019OAI: oai:DiVA.org:liu-71941DiVA: diva2:455498
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Immune profile from high-risk to onset of Type 1 diabetes
Open this publication in new window or tab >>Immune profile from high-risk to onset of Type 1 diabetes
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is most often diagnosed early in life and is usually the result of an autoimmune attack on the insulin producing β-cells of the pancreas, leading to a lack of insulin secretion and life-long insulin treatment. The search for possible targets pin-pointing the β-cell destruction is a constant endeavour in the pursuit to prevent T1D onset. Hence, characterisation of the immunological profile and changes therein, during the pre-diabetic phase and disease course, is of outmost importance for the understanding of the immunological processes involved in T1D pathogenesis.

The aim of this thesis was to investigate the immunological profile, focusing on markers associated with T helper (Th) cells, pro-inflammation and regulatory T cells (Treg), in individuals with a high risk of developing T1D, and in children with newly diagnosed T1D for up to two years post diagnosis. In addition, we wanted to efficiently expand Tregs and detect any difference in T cell number and composition among T1D, high-risk and healthy individuals.

We found that high-risk individuals that later developed T1D had a lower mRNA expression of the regulatory associated markers forkhead box protein 3 (FOXP3), cytotoxic T lymphocyte associated antigen (CTLA)-4 and transforming growth factor (TGF)-β, following stimulation with the major autoantigen glutamic acid decarboxylase (GAD)65, in combination with higher secretions of the chemotactic pro-inflammatory cytokine machrophage inflammatory protein (MIP)-1β, in comparison with high-risk individuals remaining undiagnosed.

In addition to a markedly altered immune profile during the pre-diabetic phase, T1D seems to present with an intense up-regulation of regulatory (FOXP3, TGF-β and CTLA-4) and pro-inflammatory (e.g. tumour necrosis factor-α) markers and a suppression of Th1 (e.g. interferon-γ) and Th2-associated immunity (e.g. interleukin-13). This up-regulation of regulatory markers, however, seems to occur too late in the immunological process to suppress the autoimmune attack directed against the pancreatic β-cells, and is probably reflecting the strong activation seen at onset of disease, rather than a cause of disease. Furthermore, we found low levels of circulating soluble CTLA-4 together with a positive correlation between soluble CTLA-4 protein secretion and mRNA expression in T1D, in parallel to a negative relation in healthy individuals. Moreover, low C-peptide was accompanied by low mitogen-induced soluble CTLA-4 protein, and vice versa, pointing to a link between clinical process, i.e. β-cell degradation and ability to secrete the regulatory molecule soluble CTLA-4 upon mitosis.

Our study also suggests that T1D children in our cohort were associated with a lower percentage of CD4+CD25+CD127lo/-Tregs, however, the ones they had expanded well and even acquired a higher FOXP3 expression. We found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs.

In conclusion, the pre-diabetic phase seems to be accompanied by lower mRNA expression of regulatory associated markers in combination with higher secretions of the chemotactic pro-inflammatory cytokine MIP-1β, acknowledging the importance of studying this period in order to characterise the origin of T1D development. In addition, T1D seems to present with an intense up-regulation of regulatory and pro-inflammatory markers and a suppression of Th1 and Th2-associated immunity followed by low levels of circulating soluble CTLA-4 and, suggestively, lower percentage of CD4+CD25+CD127lo/-Tregs. Whereas we found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs, the importance of said alteration remains to be shown.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 101 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1275
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71947 (URN)978-91-7393-025-3 (ISBN)
Public defence
2011-12-09, Berzeliussalen, Hälsouniversitetet, CampusUS, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2011-11-10Bibliographically approved

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Rydén, AnnaFaresjö, Maria

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