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- Hässler, Signe, et al.
(författare)
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Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes
- 2008
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 67:6, s. 569-580
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Tidskriftsartikel (refereegranskat)abstract
- Aire-deficient mice are a model of the human monogenic disorder autoimmune polyendocrine syndrome type I (APS I) characterized by a progressive autoimmune destruction of multiple endocrine glands such as the adrenal cortex, the parathyroids and the beta-cells of the pancreas. The disease is caused by mutations in the autoimmune regulator (AIRE) gene, a putative transcription factor expressed in thymic medullary epithelial cells and in antigen-presenting cells of the myeloid lineage in peripheral lymphoid organs. As Aire(-/-) mice do not spontaneously develop endocrinopathies, we wanted to evaluate the autoimmune multiple low-dose streptozotocin (MLDSTZ) diabetes model in Aire(-/-) mice. Surprisingly, Aire heterozygote mice were most susceptible to MLDSTZ-induced diabetes, whereas Aire(-/-) mice displayed an intermediate sensitivity to diabetes. Furthermore, Aire(-/-) macrophages produced higher levels of TNF-alpha and lower levels of IL-10 following streptozotocin stimulation, and Aire(-/-) mice developed a higher frequency of islet cells autoantibodies as a sign of increased activation. However, the number of islet infiltrating F4/80(+) Aire(-/-) macrophages was significantly decreased which was attributed to an increased susceptibility to streptozotocin cytotoxicity of Aire(-/-) macrophages. In conclusion, Aire(-/-) macrophages display an increased activation after STZ stimuli, but suffer from increased susceptibility to STZ cytotoxicity. These results support an important function of Aire in the control of peripheral tolerance through myeloid antigen-presenting cells.
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- Karlsson, Maria G. E.
(författare)
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The Importance of Cell-Mediated Immunity for the Development of Type 1 Diabetes
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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