Abstract
Type 1 diabetes is caused by death of insulin-producing pancreatic beta cells. Beta-cell apoptosis induced by FasL may be important in type 1 diabetes in humans and in the non-obese diabetic (NOD) mouse model. Deficiency of the pro-apoptotic BH3-only molecule Bid protects beta cells from FasL-induced apoptosis in vitro. We aimed to test the requirement for Bid, and the significance of Bid-dependent FasL-induced beta-cell apoptosis in type 1 diabetes. We backcrossed Bid-deficient mice, produced by homologous recombination and thus without transgene overexpression, onto a NOD genetic background. Genome-wide single nucleotide polymorphism analysis demonstrated that diabetes-related genetic regions were NOD genotype. Transferred beta cell antigen-specific CD8+ T cells proliferated normally in the pancreatic lymph nodes of Bid-deficient mice. Moreover, Bid-deficient NOD mice developed type 1 diabetes and insulitis similarly to wild-type NOD mice. Our data indicate that beta-cell apoptosis in type 1 diabetes can proceed without Fas-induced killing mediated by the BH3-only protein Bid.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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BH3 Interacting Domain Death Agonist Protein / deficiency
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BH3 Interacting Domain Death Agonist Protein / metabolism*
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CD4 Antigens / metabolism
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / physiology
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Cell Proliferation
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Cells, Cultured
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DNA Fragmentation
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / metabolism*
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Fas Ligand Protein / pharmacology
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Fas Ligand Protein / physiology
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Female
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Forkhead Transcription Factors / metabolism
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Immune System / cytology
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Immunophenotyping
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Interferon-gamma / pharmacology
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Interferon-gamma / physiology
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Interleukin-1beta / pharmacology
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Interleukin-1beta / physiology
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Islets of Langerhans / immunology*
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
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fas Receptor / metabolism
Substances
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BH3 Interacting Domain Death Agonist Protein
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Bid protein, mouse
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CD4 Antigens
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Fas Ligand Protein
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Fas protein, mouse
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Fasl protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-1beta
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Tumor Necrosis Factor-alpha
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fas Receptor
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Interferon-gamma