Role of defective apoptosis in type 1 diabetes and other autoimmune diseases.
Lymphocyte development, selection, and education are strictly controlled to prevent autoimmunity, with potentially autoreactive cells being removed by apoptosis. Dysregulation of apoptosis is a central defect in diverse murine autoimmune diseases. In murine models of autoimmune lupus, for example, mutations in the death receptor Fas (CD95) or in its ligand, FasL (CD95L), have been identified and shown to render lymphoid cells resistant to apoptosis. In contrast, select lymphoid subpopulations of mice with autoimmune diabetes manifest an increased susceptibility to apoptosis as a result of impaired activation of the transcription factor nuclear factor-kappa B (NF-kappaB), which normally protects cells against tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. The genetic basis of this defect in NF-kappaB activation is a mutation in the promoter-enhancer region of a gene that encodes an essential subunit (LMP2) of the proteasome. Although no specific genetic defects have been identified in most common forms of human autoimmune disease, functional assays consistently demonstrate heightened apoptosis attributable to multiple death signaling pathways.
Hayashi
Takuma
T
Immunobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Faustman
Denise L
DL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D009097:Multienzyme Complexes / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D009097:Multienzyme Complexes; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex