Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA.
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| 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.
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| Authors | Hiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, Katsushi Tokunaga |
| Journal | The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 1 Pg. 275-91 (Jan 2015) ISSN: 1558-8238 [Electronic] United States |
| PMID | 25485681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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