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

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Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. / Miyadera, Hiroko; Ohashi, Jun; Lernmark, Åke; Kitamura, Toshio; Tokunaga, Katsushi.

In: Journal of Clinical Investigation, Vol. 125, No. 1, 2015, p. 275-291.

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Miyadera, Hiroko ; Ohashi, Jun ; Lernmark, Åke ; Kitamura, Toshio ; Tokunaga, Katsushi. / Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 1. pp. 275-291.

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TY - JOUR

T1 - Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA

AU - Miyadera, Hiroko

AU - Ohashi, Jun

AU - Lernmark, Åke

AU - Kitamura, Toshio

AU - Tokunaga, Katsushi

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1172/JCI74961

DO - 10.1172/JCI74961

M3 - Article

C2 - 25485681

VL - 125

SP - 275

EP - 291

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -