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Peptide from glutamic acid decarboxylase similar to coxsackie B virus stimulates IFN- γ mRNA expression in Th1-like lymphocytes from children with recent-onset insulin-dependent diabetes mellitus
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
1998 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 35, no 3, 137-144 p.Article in journal (Refereed) Published
Abstract [en]

At the clinical onset of insulin-dependent diabetes mellitus (type 1 diabetes), inflammation within the pancreatic islets of Langerhans causes insulitis. CD4+ or Th-lymphocytes will be activated after stimulation resulting in interferon-gamma (IFN-γ) production by Th1-like lymphocytes and/or interleukin-4 (IL-4) secretion from Th2-like lymphocytes. The antigens responsible for this activation are unknown, but studies have suggested glutamic acid decarboxylase (GAD) to be a possible candidate. One peptide from this enzyme (amino acid 247–279) with a similar amino acid sequence to coxsackie B virus may cause lymphocyte proliferation in diabetic patients. In this study we have shown that this peptide activates Th1-like lymphocytes which produce increased amounts of IFN-γ mRNA, but seldom mRNA for IL-4. Lymphocytes from healthy HLA-matched controls (DR3/4) did not respond with an upregulated mRNA expression for these cytokines when stimulated by the GAD-peptide (P<0.05). A low or absent expression of IFN-γ mRNA was significantly correlated to a high fasting C-peptide at 3 months' duration (P<0.05). In conclusion, we suggest that GAD65 is involved in the development of type 1 diabetes and that the Th1-response may play a role in the destruction of β cells.

Place, publisher, year, edition, pages
1998. Vol. 35, no 3, 137-144 p.
Keyword [en]
Th-lymphocytes, IFN-γ, mRNA, GAD65, coxsackie B virus
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-79851DOI: 10.1007/s005920050118PubMedID: 9840449OAI: oai:DiVA.org:liu-79851DiVA: diva2:544410
Available from: 2012-08-14 Created: 2012-08-14 Last updated: 2017-12-07Bibliographically approved
In thesis
1. The Importance of Cell-Mediated Immunity for the Development of Type 1 Diabetes
Open this publication in new window or tab >>The Importance of Cell-Mediated Immunity for the Development of Type 1 Diabetes
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Type I (insulin-dependent) diabetes mellitus is an autoimmune disease characterised by infiltration of T-lymphocytes in the islets of Langerhans. In particular, activated Th1-like lymphocytes secreting IFN-γ are suggested to contribute to the inflammatory process and the destruction of ß-cells, whereas Th2-like cells producing IL-4 might even be protective. Environmental factors (diet, viruses, stress etc.) and autoantigens, e.g. Glutamic Acid Decarboxylase (GAD65) and insulin, are suggested to initiate the autoimmune process resulting in type I diabetes.

Aim To estimate the immunological balance of Th1/Th2-like lymphocytes, spontaneously and after stimulation with antigens, in high-risk first degree relatives of type 1 diabetic children and in children with newly diagnosed type 1 diabetes.

Materials and methods Peripheral blood mononuclear cells (PBMC) from healthy high-risk first-degree relatives (ICA ≥ 20) and newly diagnosed type 1 diabetic children were examined and compared with the response seen in PBMC from healthy controls matched for age and HLA-type (DR3 and/or DR4).

Expression of IFN-γ and IL-4 mRNA was determined by RT-PCR or real-time RTPCR and IFN-γ and IL-4 by ELISPOT or ELISA, spontaneously and after stimulation with GAD65 , insulin, bovine serum albumin (BSA), the ABBOS-peptide and ß-lactoglobulin (ßLG). Cytokine expression and secretion was compared to the production of diabetes-associated autoantibodies and to the secretion of endogenous insulin.

Results The epitope of GAD65, that mimics the Coxsackie B virus, caused increased IFN-γ mRNA expression in activated Th1-like lymphocytes from newly diagnosed diabetic children. This suggests that GAD65 might be involved in the development of type I diabetes. On the contrary, cow's milk proteins caused increased IFN-γ and IL- 4 mRNA expression in activated Th1- and Th2-like lymphocytes from both diabetic and healthy children. This does not support the hypothesis that cow's milk antigens are important for the development of type 1 diabetes.

Overwhelming secretion of IFN-γ was observed in high-risk first-degree relatives of type 1 diabetic children. High-risk individuals still have the ability to change a Th1-like immune deviation into a more protective Th2-like response in the presence of GAD65 and insulin.

Conclusions GAD65, but not cow's milk proteins, causes a Th1-like deviation in type 1 diabetic children. High-risk individuals are capable to deviate a Th1-like immune system into a more protective Th2-like response in the presence of autoantigens. These results can be useful in future therapeutic approaches.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2000. 130 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 644
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28590 (URN)13744 (Local ID)91-7219-745-5 (ISBN)13744 (Archive number)13744 (OAI)
Public defence
2000-10-20, Berzeliussalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-08-14Bibliographically approved

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