PDF(Pubmed)
Abstract：
Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.
摘要：
特异性人类白细胞抗原（HLA）多态性与某些药物给药密切相关。阿巴卡韦超敏反应（AHS），与HLA-B*57:01密切相关，是最具代表性的例子之一。传统上,HLA通过与细胞表面T细胞受体的相互作用传递免疫信号。这项研究集中在角质形成细胞中HLA介导的细胞内反应，这些反应可能决定药物治疗引起的皮肤免疫毒性。阿巴卡韦暴露导致表达HLA-B*57:01的角质形成细胞表现出内质网（ER）应激反应，例如立即将钙释放到细胞质中并增强HSP70表达。相比之下,表达HLA-B*57:03(与HLA-B*57:01密切相关)的角质形成细胞没有显示这些变化。这表明在缺乏淋巴细胞的情况下,HLA-B*57:01对角质形成细胞中的阿巴卡韦具有特异性细胞内应答。此外，abacavir暴露在HLA-B*57:01-表达角质形成细胞升高细胞因子/趋化因子如干扰素-γ的表达，白细胞介素-1β，和CCL27，并诱导T淋巴母细胞迁移。通过使用4-苯基丁酸酯(4-PB)的ER应激缓解来抑制这些作用。HLA-B*57：01转基因小鼠在阿巴卡韦给药后也表现出表皮区域的ER应激，阿巴卡韦诱导的皮肤毒性通过4-PB的给药减弱。此外，阿巴卡韦与细胞内的HLA-B*57：01结合，其暴露导致HLA-B*57：01蛋白质聚集并与角质形成细胞ER中的分子伴侣相互作用。我们的结果强调了HLA介导的细胞内应激反应在理解HLA-B*57：01介导的AHS发作中的重要性。我们提供了HLA的细胞内行为对于确定药疹发作至关重要的可能性。
