Functional Consequences of HLA-DQ8 Homozygosity Versus Heterozygosity for Islet Autoimmunity in Type 1 Diabetes

Genes Immun. 2011 Sep;12(6):415-27. doi: 10.1038/gene.2011.24. Epub 2011 May 12.

Abstract

Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Epitopes, B-Lymphocyte / immunology
  • Genetic Predisposition to Disease
  • HLA-DQ Antigens / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Insulin / genetics
  • Islets of Langerhans / immunology*
  • Male
  • Protein Binding
  • Syndecans / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Thymosin / metabolism

Substances

  • Epitopes, B-Lymphocyte
  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ6 antigen
  • HLA-DQ8 antigen
  • Insulin
  • Syndecans
  • thymosin beta(4)
  • Thymosin