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PMID: 25485681 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA.

The Journal of clinical investigation ·Vol. 125 ·No. 1 ·2015-01-00 ·Pages 275-91

Miyadera H, Ohashi J, Lernmark Å, Kitamura T, Tokunaga K

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.

MeSH Terms
Amino Acid Substitution Animals Case-Control Studies Cell Membrane/metabolism Diabetes Mellitus, Type 1/genetics,metabolism Evolution, Molecular Gene Frequency Genetic Predisposition to Disease HLA-DQ Antigens/genetics,metabolism Humans Mice NIH 3T3 Cells Polymorphism, Genetic Protein Stability
Chemicals
HLA-DQ Antigens
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Miyadera Hiroko
Ohashi Jun
Lernmark Åke
Kitamura Toshio
Tokunaga Katsushi
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI74961
Published
2015-01-00
Epub
2014-00-08
Pages
275-91
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC4382229
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI74961 PMC Full Text View journal details
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