title: Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.
abstract: A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Norio
authors.initials: N
authors.lastname: Abiru
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Naru
authors.initials: N
authors.lastname: Babaya
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Miao
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Dale R
authors.initials: DR
authors.lastname: Wegmann
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.forename: John F
authors.initials: JF
authors.lastname: Elliott
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001786:Blood Glucose / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology*; D005260:Female; D007328:Insulin / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001786:Blood Glucose; D000939:Epitopes; D007328:Insulin; D011384:Proinsulin