Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity.
Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity.
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DOI：
10.1097/qad.0b013e328355fe8f
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发表时间：
2012-07-17
期刊：
影响因子：
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通讯作者：
Buchli R
中科院分区：
文献类型：
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作者：
Norcross MA;Luo S;Lu L;Boyne MT;Gomarteli M;Rennels AD;Woodcock J;Margulies DH;McMurtrey C;Vernon S;Hildebrand WH;Buchli R
HIV治疗患者的阿巴卡韦药物超敏反应与HLA-B*57：01表达相关为了了解阿巴卡韦药物反应的免疫化学，我们研究了阿巴卡韦对体外HLA-B*57：01表位结合的影响以及阿巴卡韦处理的细胞中HLA-B*57：01呈递的自身肽的质量和数量。开发了HLA-B*57：01特异性表位结合测定以测试阿巴卡韦、去羟肌苷或氟氯西林对自身肽结合的影响。为了检查阿巴卡韦是否改变HLA-B*57：01中的肽库，在存在或不存在阿巴卡韦的情况下培养分泌可溶性人白细胞抗原（sHLA）的B细胞系，从纯化的人白细胞抗原（HLA）洗脱肽，并通过质谱比较绘制肽表位以鉴定药物独特的肽。阿巴卡韦，而不是didansosine或氟氯西林，增强了FITC标记的自身肽LF 9与HLA-B*57：01的结合，以剂量依赖性的方式。从阿巴卡韦处理的HLA-B *57：01 B细胞中分离的内源性肽与来自未处理细胞的肽相比显示氨基酸序列差异。新型药物诱导肽缺乏HLA-B*57：01肽基序的典型羧基（C）末端氨基酸特征，而是主要含有异亮氨酸或亮氨酸残基。药物诱导的肽以高亲和力结合可溶性HLA-B*57：01，其不被阿巴卡韦添加改变。我们的研究结果支持了药物诱导的自身免疫模型，其中阿巴卡韦改变了装载到HLA-B*57：01中的自身肽的数量和质量。可能通过阿巴卡韦改变结合裂缝或修饰肽加载复合物，药物诱导的新自身肽加载到HLA中，产生一系列新抗原肽，其驱动多克隆T细胞自身免疫应答和多器官全身毒性。
Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B*57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B*57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B*57:01 from abacavir-treated cells. An HLA-B*57:01-specific epitope-binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B*57:01, a B-cell line secreting soluble human leucocyte antigen (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified human leucocyte antigen (HLA), and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides. Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC-labeled self-peptide LF9 to HLA-B*57:01 in a dose-dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B*57:01 B cells showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical carboxyl (C) terminal amino acids characteristic of the HLA-B*57:01 peptide motif and instead contained predominantly isoleucine or leucine residues. Drug-induced peptides bind to soluble HLA-B*57:01 with high affinity that was not altered by abacavir addition. Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B*57:01. Drug-induced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide-loading complex, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity.