Comprehensive assessment of T cell receptor β repertoire in Stevens-Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing
Comprehensive assessment of T cell receptor β repertoire in Stevens-Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing
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DOI：
10.1016/j.molimm.2019.01.002
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发表时间：
2019-02-01
影响因子：
3.6
通讯作者：
Luo, Xiaoqun
中科院分区：
文献类型：
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作者：
Xiong, Hao;Wang, Lanting;Luo, Xiaoqun
史蒂文斯-约翰逊综合征(SJS)/中毒性表皮坏死松解症(TEN)是一种以广泛的表皮坏死为特征的严重皮肤不良反应，危及生命。最近的研究表明，SJS/TEN是一种由T细胞调节的特异性免疫反应。某些药物作为外来抗原，由主要组织相容性复合体(MHC)呈递并被T细胞受体(TCR)识别，从而诱导获得性免疫反应。然而，很少有研究对SJS/TEN中的TCR谱系进行详细的表征，并且尚不清楚克隆扩增的特定类型的TCR是否具有药物特异性，这可能为SJS/TEN提供潜在的潜在机制。在这项研究中，我们利用高通量测序技术，综合评估了17例SJS/TEN患者与三种不同致病药物包括甲唑胺(MZ)、卡马西平(CBZ)和别嘌醇(ALP)相关的TCRβ谱系的多样性、组成和分子特征。对TCRβ序列的系统分析表明，SJS/TEN患者具有较高的克隆扩增和较低的TCR谱系多样性，且这些患者的TCR谱系多样性与疾病的临床严重程度有一定的相关性。相同病原体的不同受试者之间存在相似的优势克隆型、共同使用的TRBV/TRBJ亚型及其组合。我们的观察加深了对T淋巴细胞在SJS/TEN发病机制中作用的理解，并列举了潜在的治疗靶点。
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCR beta repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCR beta sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.