Cell-surface MHC Density Profiling Reveals Instability of Autoimmunity-Associated HLA

J Clin Invest. 2015 Jan;125(1):275-91. doi: 10.1172/JCI74961. Epub 2014 Dec 8.

Abstract

Polymorphisms within HLA gene loci are strongly associated with susceptibility to autoimmune disorders; however, it is not clear how genetic variations in these loci confer a disease risk. Here, we devised a cell-surface MHC expression assay to detect allelic differences in the intrinsic stability of HLA-DQ proteins. We found extreme variation in cell-surface MHC density among HLA-DQ alleles, indicating a dynamic allelic hierarchy in the intrinsic stability of HLA-DQ proteins. Using the case-control data for type 1 diabetes (T1D) for the Swedish and Japanese populations, we determined that T1D risk-associated HLA-DQ haplotypes, which also increase risk for autoimmune endocrinopathies and other autoimmune disorders, encode unstable proteins, whereas the T1D-protective haplotypes encode the most stable HLA-DQ proteins. Among the amino acid variants of HLA-DQ, alterations in 47α, the residue that is located on the outside of the peptide-binding groove and acts as a key stability regulator, showed strong association with T1D. Evolutionary analysis suggested that 47α variants have been the target of positive diversifying selection. Our study demonstrates a steep allelic hierarchy in the intrinsic stability of HLA-DQ that is associated with T1D risk and protection, suggesting that HLA instability mediates the development of autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Case-Control Studies
  • Cell Membrane / metabolism*
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Evolution, Molecular
  • Gene Frequency
  • Genetic Predisposition to Disease
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / metabolism*
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Polymorphism, Genetic
  • Protein Stability

Substances

  • HLA-DQ Antigens