title: The pro-apoptotic BH3-only protein Bid is dispensable for development of insulitis and diabetes in the non-obese diabetic mouse.
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.
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
authors.forename: Zia U A
authors.initials: ZU
authors.lastname: Mollah
authors.forename: Jibran
authors.initials: J
authors.lastname: Wali
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKenzie
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.forename: Stacey
authors.initials: S
authors.lastname: Fynch
authors.forename: Joshua
authors.initials: J
authors.lastname: Szanyi
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Thomas
authors.initials: T
authors.lastname: Brodnicki
authors.forename: Janette
authors.initials: J
authors.lastname: Allison
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D053938:DNA Fragmentation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000494:pharmacology / Q000502:physiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007107:Immune System / Q000166:cytology; D016130:Immunophenotyping; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D015704:CD4 Antigens; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma