RRC ID 45404
Author Miyadera H, Ohashi J, Lernmark Å, Kitamura T, Tokunaga K.
Title Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA.
Journal J Clin Invest
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.
Volume 125(1)
Pages 275-91
Published 2015-1-1
DOI 10.1172/JCI74961
PII 74961
PMID 25485681
PMC PMC4382229
MeSH 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
IF 11.864
Times Cited 37
Human and Animal Cells NIH3T3-3-4(RCB1862)