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Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
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2012 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 28, no 1, 84-96 p.Article in journal (Refereed) Published
Abstract [en]

High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full length CTLA-4 and other Treg associated markers in T1D children and in individuals with high or low risk of developing the disease.

T1D children were studied at four days, one and two years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells (PBMC) were stimulated with the T1D-associated glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA). Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.

Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel to a negative relation in healthy subjects. Further, low mitogen-induced soluble CTLA-4 was accompanied by low C-peptide, together indicating an inverse relation of soluble CTLA-4 between health and disease. Moreover, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high-risk individuals, indicating an alteration in activation and downregulating immune mechanisms already during the pre-diabetic phase.

Place, publisher, year, edition, pages
Wiley , 2012. Vol. 28, no 1, 84-96 p.
Keyword [en]
soluble CTLA-4; PBMC; Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71942DOI: 10.1002/dmrr.1286ISI: 000298736800008OAI: oai:DiVA.org:liu-71942DiVA: diva2:455503
Note
funding agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Schelin Foundation||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)
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Supervisors
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2011-11-10Bibliographically approved

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Rydén, AnnaJonson, Carl-OscarFaresjö, Maria

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