Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

被引:64
作者
Durinovic-Bello, I. [1 ]
Wu, R. P. [1 ]
Gersuk, V. H. [1 ]
Sanda, S. [1 ]
Shilling, H. G. [1 ]
Nepom, G. T. [1 ]
机构
[1] Univ Washington, Sch Med, Benaroya Res Inst, Seattle, WA 98101 USA
关键词
autoimmune diabetes; insulin; proinsulin; INS-VNTR; genotype; tetramer; CLASS-II TETRAMERS; T-CELL EPITOPES; HUMAN THYMUS; NOD MICE; TYPE-1; INDIVIDUALS; EXPRESSION; ALLELES; LOCUS; RISK;
D O I
10.1038/gene.2009.108
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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. Genes and Immunity (2010) 11, 188-193; doi: 10.1038/gene.2009.108; published online 7 January 2010
引用
收藏
页码:188 / 193
页数:6
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