Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema
Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema
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DOI：
10.1111/all.13847
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发表时间：
2019-09-01
期刊：
影响因子：
12.4
通讯作者：
Fernandez, Tahia D.
中科院分区：
文献类型：
--
作者：
Fernandez-Santamaria, Ruben;Palomares, Francisca;Fernandez, Tahia D.
药物诱导的斑丘疹样增生（MPE）是由Th 1 CD 4（+）T细胞介导的。控制Th 1细胞稳态的机制之一是检查点抑制剂Tim 3与其生理配体半乳糖凝集素-9（Gal 9）之间的相互作用。影响该轴的疾病可能是各种自身免疫性和免疫性疾病的原因。本研究的目的是确定Tim 3-Gal 9轴对药物诱导的MPE发展的影响。方法采用流式细胞术和免疫组化法分别检测不同类型的淋巴细胞在正常人外周血和皮肤组织中的分布及Tim 3和Gal 9的表达。通过RT-qPCR评估Gal 9表达;通过多重测定测量其释放。通过流式细胞术测定阻断或增强Tim 3-Gal 9轴对单核细胞衍生的树突状细胞（moDC）成熟和T细胞增殖的影响。结果与对照组相比，MPE患者外周血Th 1细胞和皮肤中Tim 3的表达明显降低。Gal 9表达和释放分别在患者外周血和moDC中显著降低。外源性Gal 9的加入显著降低了Tim 3（+）Th 1的增殖，尽管Treg的增殖增加。结论本研究提示Tim 3-Gal 9轴参与MPE的发生。Th 1细胞中Tim 3的表达减少以及PBMC和DC中Gal 9的表达受损似乎在疾病的发展中起作用。Gal 9抑制Th 1和增强Treg增殖的潜力使其成为治疗这些反应的有希望的工具。
Background Drug-induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4(+) T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin-9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3-Gal9 axis on the development of MPE induced by drugs. Methods Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT-qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3-Gal9 axis on monocyte-derived dendritic cell (moDC) maturation and T-cell proliferation were determined by flow cytometry. Results The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3(+) Th1 proliferation, although Treg proliferation increased. Conclusion This study showed the involvement of the Tim3-Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.