The role of the proteasome in autoimmunity.
Type 1 diabetes is believed to be caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of Type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has now been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays an important role in immune and inflammatory responses, in addition to increasing the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The proteasome dysfunction is both tissue- and developmental stage-specific and likely contributes to disease pathogenesis and tissue targeting.
Hayashi
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Immunobiology Laboratory, Massachusetts General Hospital, and Harvard Medical School, Charlestown, MA 02129, USA.
Faustman
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D
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D003546:Cysteine Endopeptidases / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D009097:Multienzyme Complexes / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex