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

Genes Immun. 2010 Mar;11(2):188-93. doi: 10.1038/gene.2009.108. Epub 2010 Jan 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens / immunology
  • Autoimmunity / immunology*
  • Diabetes Mellitus, Type 1 / genetics
  • Disease Susceptibility / immunology
  • Genotype*
  • Histocompatibility Antigens Class II / genetics
  • Humans
  • Insulin / genetics*
  • Minisatellite Repeats / genetics*
  • Phenotype
  • Polymorphism, Genetic
  • Proinsulin / genetics
  • Proinsulin / immunology*
  • T-Lymphocytes / immunology


  • Autoantigens
  • Histocompatibility Antigens Class II
  • Insulin
  • Proinsulin