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Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Charles University Prague.
Charles University Prague.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2009 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, 335-343 p.Article in journal (Refereed) Published
Abstract [en]

Background: Type 1 diabetes (T1D) is all autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This Study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the Study focused on spontaneous as well as autoantigen-induced immune profile.

Methods: Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA andgt;= 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, turnout necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).

Results: High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.

Conclusion: A dominant Thl-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.

Place, publisher, year, edition, pages
2009. Vol. 25, no 4, 335-343 p.
Keyword [en]
Type 1 diabetes, high-risk children, T-helper cells, T-regulatory cells, cytokines, chemokines
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19142DOI: 10.1002/dmrr.958OAI: oai:DiVA.org:liu-19142DiVA: diva2:223402
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically 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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