Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA
Miyadera, Hiroko ; Ohashi, Jun ; Lernmark, Åke LU
; Kitamura, Toshio
and Tokunaga, Katsushi
(2015)
In Journal of Clinical Investigation
125(1).
p.275-291
- 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... (More)
- 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 47 alpha, 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 47 alpha 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5070014
- author
- Miyadera, Hiroko
; Ohashi, Jun
; Lernmark, Åke
LU
; Kitamura, Toshio
and Tokunaga, Katsushi
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 125
- issue
- 1
- pages
- 275 - 291
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- wos:000347747300031
- scopus:84920381515
- pmid:25485681
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI74961
- language
- English
- LU publication?
- yes
- id
- 58b8ba66-9776-4bf3-a2ad-01658304ed2b (old id 5070014)
- date added to LUP
- 2016-04-01 13:09:55
- date last changed
- 2022-03-29 05:56:28
@article{58b8ba66-9776-4bf3-a2ad-01658304ed2b,
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 47 alpha, 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 47 alpha 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.}},
author = {{Miyadera, Hiroko and Ohashi, Jun and Lernmark, Åke and Kitamura, Toshio and Tokunaga, Katsushi}},
issn = {{0021-9738}},
language = {{eng}},
number = {{1}},
pages = {{275--291}},
publisher = {{The American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA}},
url = {{https://lup.lub.lu.se/search/files/3198714/7761776}},
doi = {{10.1172/JCI74961}},
volume = {{125}},
year = {{2015}},
}