title: Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin.
abstract: Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76-90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a 'protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens.
authors.affiliation: Benaroya Research Institute, University of Washington School of Medicine, 1201 Ninth Avenue, Seattle, WA 98101-2795, USA. ibello@benaroyaresearch.org
authors.forename: I
authors.initials: I
authors.lastname: Durinovic-Belló
authors.forename: R P
authors.initials: RP
authors.lastname: Wu
authors.forename: V H
authors.initials: VH
authors.lastname: Gersuk
authors.forename: S
authors.initials: S
authors.lastname: Sanda
authors.forename: H G
authors.initials: HG
authors.lastname: Shilling
authors.forename: G T
authors.initials: GT
authors.lastname: Nepom
mesh_terms: D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D004198:Disease Susceptibility / Q000276:immunology; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics*; D018598:Minisatellite Repeats / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011384:Proinsulin / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D011384:Proinsulin