title: A defect in central tolerance in NOD mice.
abstract: The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IAbetag7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor-mediated up-regulation of caspase 8-homologous FLICE (Fas-associated death-domain-like interleukin 1beta-converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.
authors.affiliation: Department of Immunology, IMM4, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kishimoto
authors.forename: J
authors.initials: J
authors.lastname: Sprent
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D017637:Clonal Deletion / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance / Q000276:immunology*; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD / Q000235:genetics / Q000276:immunology*; D008814:Mice, Inbred NZB; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology*; D019014:fas Receptor / Q000502:physiology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D002352:Carrier Proteins; D053222:Fas Ligand Protein; D015847:Interleukin-4; D015851:Interleukin-7; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D000099192:CD69 Antigens; C506387:Cflar protein, mouse; C505658:Fasl protein, mouse