Central role of defective apoptosis in autoimmunity.
Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) that normally protect against apoptotic death. The genetic basis of interrupted NF-kappaB in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.
Kühtreiber
W M
WM
Immunobiology Laboratory, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Hayashi
T
T
Dale
E A
EA
Faustman
D L
DL
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D008177:Lupus Vulgaris / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019014:fas Receptor; D046988:Proteasome Endopeptidase Complex