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Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA
Hiroko Miyadera, … , Toshio Kitamura, Katsushi Tokunaga
Hiroko Miyadera, … , Toshio Kitamura, Katsushi Tokunaga
Published December 8, 2014
Citation Information: J Clin Invest. 2015;125(1):275-291. https://doi.org/10.1172/JCI74961.
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Research Article Immunology Article has an altmetric score of 13

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.

Authors

Hiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, Katsushi Tokunaga

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Figure 2

ΔMHC profile for the HLA-DQ allele products.

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ΔMHC profile for the HLA-DQ allele products.
(A) ΔMHC profile for HLA-DQ...
(A) ΔMHC profile for HLA-DQ. Numbers and color scale indicate the ΔMHC (normalized to the ΔMHC of DQ0602). ΔMHC values below the threshold (<0.005 after normalization) are blank. Graphs display the ΔMHC value for each subgroup. Error bars represent the SEM. See also Supplemental Table 1. (B and C) ΔMHC profiles for the major HLA-DQ allele products (B) and the major DQ haplotype products (C). In C, the DQ haplotypes that are present at a haplotype frequency greater than 0.03 in at least 1 of the following populations are magenta colored: Congo Kinshasa Bantu (n = 90) (122, 135); Tunisian (n = 100) (122); South Korean (n = 324) (122); Indian Uttar Pradesh (n = 202) (122, 136); and European-American (n = 1,899) (133).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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