論文 - 詳細
| RRC ID | 45404 |
|---|---|
| 著者 | Miyadera H, Ohashi J, Lernmark Å, Kitamura T, Tokunaga K. |
| タイトル | Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. |
| ジャーナル | J Clin Invest |
| 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. |
| 巻・号 | 125(1) |
| ページ | 275-91 |
| 公開日 | 2015-1-1 |
| DOI | 10.1172/JCI74961 |
| PII | 74961 |
| PMID | 25485681 |
| PMC | PMC4382229 |
| MeSH | Amino Acid Substitution Animals Case-Control Studies Cell Membrane / metabolism* Diabetes Mellitus, Type 1 / genetics* Diabetes Mellitus, Type 1 / metabolism Evolution, Molecular Gene Frequency Genetic Predisposition to Disease HLA-DQ Antigens / genetics HLA-DQ Antigens / metabolism* Humans Mice NIH 3T3 Cells Polymorphism, Genetic Protein Stability |
| IF | 11.864 |
| 引用数 | 37 |
| WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 12 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | NIH3T3-3-4(RCB1862) |