Department of Mycobacterium, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology & Hospital for Skin Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
J Biomed Sci. 2022 Aug 13;29(1):58. doi: 10.1186/s12929-022-00845-8.
Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized.
To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS.
Results showed the crystal structure of HLA-B13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS.
Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS.
严重的皮肤药物不良反应（SCARs）是一组由某些药物的免疫反应引起的严重临床病症。人类白细胞抗原 HLA-B13:01 的等位基因变异与导致对氨苯砜（DDS）过敏的情况有很强的关联。T 细胞受体介导的细胞毒性 T 淋巴细胞（CTLs）的激活也被认为在 SCARs 的发病机制中起重要作用。然而，在药物诱导的超敏反应综合征（DIHS）相关 T 细胞激活中发挥作用的 HLA-B13:01-DDS-TCR 免疫突触仍未被描述。
为了研究 HLA-B*13:01 在 DDS 诱导的药物过敏（DDS-DIHS）发病机制中的分子机制，我们进行了结晶和扩展药物特异性 CTL 以分析 DDS-DIHS 的病理作用。
结果显示 HLA-B13:01-β2-微球蛋白（β2M）复合物的晶体结构，分辨率为 1.5Å，并进行了突变分析，证明 HLA-B13:01 的 I118 或 I119 以及 R121 是介导 DDS 结合的关键残基。随后的单细胞 TCR 和 RNA 测序表明，由 TRAV12-3/TRBV28 配对的 clonotype 组成的 TCR 与共享 CDR3 区域特异性识别 HLA-B*13:01-DDS 复合物，触发与 DDS-DIHS 相关的炎症细胞因子。
我们的研究确定了新型 p-i-HLA/TCR 作为 DDS-DIHS 中 HLA-B*13:01、DDS 和 clonotype 特异性 TCR 之间相互作用的模型。
