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

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Bibtex

@article{58b8ba6697764bf3a2ad01658304ed2b,
title = "Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA",
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 = "Hiroko Miyadera and Jun Ohashi and {\AA}ke Lernmark and Toshio Kitamura and Katsushi Tokunaga",
year = "2015",
doi = "10.1172/JCI74961",
language = "English",
volume = "125",
pages = "275--291",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "Am Soc Clin Investig",
number = "1",

}