Weak complex formation of adverse drug reaction-associated HLA B57, B58, and B15 molecules
Weak complex formation of adverse drug reaction-associated HLA B57, B58, and B15 molecules
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药物不良反应相关HLA B57、B58和B15分子的弱复合物形成
DOI：
10.1016/j.tiv.2022.105383
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发表时间：
2022
影响因子：
3.2
通讯作者：
Aoki Shigeki
中科院分区：
文献类型：
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作者：
Shirayanagi Tomohiro;Kazaoka Akira;Watanabe Kenji;Qu Liang;Sakamoto Naoki;Hoshino Tyuji;Ito Kousei;Aoki Shigeki
某些人类白细胞抗原（HLA）多态性与某些药物的施用相结合，与药物过敏的发生有很强的相关性。典型的联合例子是HLA-B*57:01与阿巴卡韦和HLA-B*15:02与卡马西平。然而，尽管属于同一血清型，HLA-B*57:03和HLA-B*15:01与药物过敏无关。最近的研究表明，几种HLA多态性与多种药物有关，而不是单一药物，所有这些都导致药物过敏。本研究比较了具有药物过敏风险的HLA-B*57:01、HLA-B*58:01和HLA-B*15:02，以及不具有药物过敏风险的HLA-B*57:03和HLA-B*15:01的分子结构和细胞内定位。我们发现存在风险的HLA分子对亚基β2微球蛋白的亲和力较低；值得注意的是，通过HLA分子Gln96形成的弱氢键有助于这种行为。我们还阐明了这些HLA分子很容易在内质网中积累，在细胞表面表现出低表达。考虑到这些超敏风险相关的HLA分子在内质网中与β2-微球蛋白和多肽形成复合物，我们假设它们在内质网中的低复合物形成能力促进了与多种药物的相互作用。
The combination of certain human leukocyte antigen (HLA) polymorphisms with administration of certain drugs shows a strong correlation with developing drug hypersensitivity. Examples of typical combinations are HLA-B*57:01 with abacavir and HLA-B*15:02 with carbamazepine. However, despite belonging to the same serotype, HLA-B*57:03 and HLA-B*15:01 are not associated with drug hypersensitivity. Recent studies have shown that several HLA polymorphisms are associated with multiple drugs rather than a single drug, all resulting in drug hypersensitivity. In this study, we compared the molecular structures and intracellular localization of HLA-B*57:01, HLA-B*58:01, and HLA-B*15:02, which pose risks for developing drug hypersensitivity, as well as HLA-B*57:03 and HLA-B*15:01 that do not present such risks. We found that HLA molecules posing risks have a low affinity for the subunit β2-microglobulin; notably, the weak hydrogen bond formed via Gln96 of the HLA molecule contributes to this behavior. We also clarified that these HLA molecules are easily accumulated in the endoplasmic reticulum, exhibiting a low expression on the cell surface. Considering that these hypersensitivity risk-associated HLA molecules form complexes with β2-microglobulin and peptides in the endoplasmic reticulum, we assumed that their low complex formation ability in the endoplasmic reticulum facilitates the interaction with multiple drugs.