TAP2 Drives HLA-B*13:01-Linked Dapsone Hypersensitivity Syndrome Tolerance and Reactivity
TAP2 Drives HLA-B*13:01-Linked Dapsone Hypersensitivity Syndrome Tolerance and Reactivity
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TAP2 驱动 HLA-B13:01 相关氨苯砜超敏综合征耐受性和反应性
DOI：
10.1016/j.jid.2022.10.009
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发表时间：
2023-04-17
影响因子：
6.5
通讯作者：
Zhang，Furen
中科院分区：
文献类型：
--
作者：
Sun，Lele;Wang，Zhenzhen;Zhang，Furen
氨苯砜过敏综合征仅限于人类白细胞抗原B∗13：01。而HLAB∗13：01的阳性预测值仅为7.8%。为了探索与DHS发生相关的潜在共存因素，我们对DHS患者和氨苯酮耐受对照组(均携带HLAB∗13：01)进行了GWADNA甲基化分析和全基因组甲基化分析。在全基因组水平上未发现与DHS相关的非HLASNPs。然而，DHS患者的抗原处理和提呈途径丰富，并发现了TAP2基因。用定量聚合酶链式反应验证TAP2及其分子伴侣TAP1的表达，并进行体外功能实验。结果显示，DHS患者TAP1、TAP2基因表达水平较高，抗原提呈细胞激活氨苯砜特异性T细胞的能力增强。当抗原提呈细胞的TAP功能受损时，氨苯酮特异性T细胞的激活受到抑制。这项研究表明，TAP1和TAP2的表观遗传调控影响抗原提呈细胞的功能，是介导DHS发生的关键因素。
Dapsone hypersensitivity syndrome (DHS) is restricted toHLA-B∗13:01. However, the positive predictive value forHLA-B∗13:01is only 7.8%. To explore the potential coexisting factors involved in the occurrence of DHS, we carried out a GWAS and a genome-wide DNA methylation profile analysis comparing patients with DHS with dapsone-tolerant control subjects (all carryingHLA-B∗13:01). No non-HLA SNPs associated with DHS were identified at the genome-wide level. However, the pathway of antigen processing and presentation was enriched in patients with DHS, and the geneTAP2was identified. Expression ofTAP2and its molecular chaperone,TAP1, were validated by quantitative PCR, and in vitro functional experiments were performed. The results showed that patients with DHS have higher mRNA levels ofTAP1andTAP2and an enhanced capacity for antigen-presenting cells activating dapsone-specific T cells compared with dapsone-tolerant controls. Activation of dapsone-specific T cells was inhibited when TAP function of antigen-presenting cells was impaired. This study shows that epigenetic regulation ofTAP1andTAP2affects the function of antigen-presenting cells and is a critical factor that mediates the development of DHS.