CCR8/CCL1 and CXCR3/CXCL10 axis mediated memory T cell activations in recalcitrant drug-induced hypersensitivity patients.

IF 11 1区 医学 Q1 DERMATOLOGY
Tsu-Man Chiu, Chun-Bing Chen, Chun-Wei Lu, Rosaline Chung-Yee Hui, Min-Hui Chi, Ya-Ching Chang, Jennifer Wu, Kuan-Yu Chen, Yang Yu-Wei Lin, Pei-Chi Lo, Tsai-Ching Hsu, Chuang-Wei Wang, Wen-Hung Chung
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Abstract

Background: As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae.

Objective: We investigated the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Methods: A total of 32 patients with recalcitrant DRESS with a prolonged treatment course ≥8 weeks, 28 patients with short-duration DRESS with a treatment course <2 weeks, and 26 healthy individuals were enrolled in the study for analysis.

Results: Bulk transcriptome results demonstrated that mRNA expression levels of CCR8 and CXCR3 were significantly increased in the blood samples from patients in the acute stage of prolonged DRESS (adjusted p-values: CCR8=1.50×10-9 and CXCR3=2.60×10-4, respectively, for comparison of patients with prolonged DRESS to the healthy donor group). Serum and skin lesional concentrations of CCL1 and CXCL10, as the ligands of CCR8 and CXCR3, respectively, were significantly elevated in patients with prolonged DRESS as compared to those patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant escalations of CD8+ GNLY+CXCR3+effector memory T cells, CD8+central memory T cells, CD4+CCR8+Th2 cells, and IgG-anti-HES6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that JAK inhibitors (mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10, and some patients with prolonged DRESS were successfully treated with JAK inhibitors.

Conclusions: JAK inhibitors (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1- and CXCR3/CXCL10-axis-mediated memory T cell activation, which contribute to disease pathogenesis for patients with recalcitrant DRESS and a long-term treatment course.

CCR8/CCL1和CXCR3/CXCL10轴介导了顽固性药物过敏症患者记忆T细胞的激活。
背景:嗜酸性粒细胞增多和全身症状的药物过敏反应(DRESS)是一种药物诱发的超敏综合征,具有潜在的致命性。大多数 DRESS 患者可在数周内痊愈,但也有一些患者病程较长,并出现自身免疫后遗症:我们研究了病程延长的顽固性DRESS患者的免疫机制和治疗靶点:共有 32 例病程≥8 周的顽固性 DRESS 患者,28 例病程短的 DRESS 患者:大量转录组结果表明,CCR8 和 CXCR3 的 mRNA 表达水平在长期 DRESS 急性期患者的血液样本中显著增加(调整后的 p 值:CCR8=1.50×10-9,CXCR3=2.60×10-4,与健康供体组进行比较)。与短期 DRESS 患者相比,长期 DRESS 患者血清和皮肤病灶中分别作为 CCR8 和 CXCR3 配体的 CCL1 和 CXCL10 浓度明显升高。高参数流式细胞术和自身抗体筛查的结果还发现,CD8+ GNLY+CXCR3+ 效应记忆 T 细胞、CD8+ 中心记忆 T 细胞、CD4+CCR8+Th2 细胞和 IgG-anti-HES6 自身抗体在长期 DRESS 患者中显著升高。此外,体外阻断试验显示,JAK抑制剂(主要是托法替尼和乌达替尼)能显著减少CCL1和CXCL10的释放,一些DRESS病程延长的患者使用JAK抑制剂治疗获得了成功:结论:JAK抑制剂(托法替尼和乌达替尼)与CCL1和CXCL10浓度的降低有关,这表明它们可能会减弱CCR8/CCL1-和CXCR3/CXCL10-轴介导的记忆性T细胞活化,这有助于顽固性DRESS患者的疾病发病机制和长期疗程。
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来源期刊
British Journal of Dermatology
British Journal of Dermatology 医学-皮肤病学
CiteScore
16.30
自引率
3.90%
发文量
1062
审稿时长
2-4 weeks
期刊介绍: The British Journal of Dermatology (BJD) is committed to publishing the highest quality dermatological research. Through its publications, the journal seeks to advance the understanding, management, and treatment of skin diseases, ultimately aiming to improve patient outcomes.
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