The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses

Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12390-5. doi: 10.1073/pnas.2135229100. Epub 2003 Oct 6.

Abstract

In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these. Moreover, gluten presentation by HLA-DQ2 homozygous antigen-presenting cells was superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells in terms of T cell proliferation and cytokine secretion. Gluten presentation by HLA-DQ2.5/2.2 heterozygous antigen-presenting cells induced intermediate T cell stimulation. These results correlated with peptide binding to the antigen-presenting cells. Finally, we demonstrate that HLA-DQ trans dimers formed in HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. Our findings explain the strongly increased risk of disease development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals, and they are indicative of a quantitative model for disease development, where HLA-DQ expression and the available number of T cell-stimulatory gluten peptides are critical limiting factors. This model may have important implications for disease prevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Base Sequence
  • Celiac Disease / genetics*
  • Celiac Disease / immunology*
  • DNA / genetics
  • Dimerization
  • Gene Dosage
  • Glutens / immunology*
  • Glutens / metabolism
  • HLA-DQ Antigens / chemistry
  • HLA-DQ Antigens / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Protein Binding
  • Risk Factors
  • T-Lymphocytes / immunology*

Substances

  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • Glutens
  • DNA