Implications of altered apoptosis in diabetes mellitus and autoimmune disease.
Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development requires cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accetuated apoptosis, are now demonstrated as central defects in diverse human and murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor CD95 (Fas) and its ligand CD95L (FasL) have been identified; these errors create a lymphoid system resistant to apoptosis. In contract, select lymphoid subpopulations of auto immune diabetic mice have accelerated apoptosis due to faulty activation of transcription factor NF-kappaB that normally protects against apoptotic death. The genetic basis of interrupted NF-kappaB in diabetes is a gene defect in an essential subunit of the proteasome. Although no specific gene in most common forms of human autoimmune disease has been identified, functional assays repeatedly demonstrate apoptotic defects in multiple cellular signaling pathways for cell death.
Hayashi
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T
Immunobiology Laboratory, Massachusetts General Hospital, and Harvard Medical School, Charlestown 02129, USA.
Faustman
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DL
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019014:fas Receptor