Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan.
Cells. 2019 Nov 13;8(11):1433. doi: 10.3390/cells8111433.
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt-AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt-AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.
T 细胞在系统性红斑狼疮（SLE）的发病机制中起着关键作用，SLE 是一种严重的自身免疫性疾病。在过去的 60 年中，仅有一种新的治疗药物被批准用于 SLE 治疗，其疗效有限；因此，SLE 的早期诊断生物标志物和治疗靶点的开发是可取的。丝裂原活化蛋白激酶激酶激酶激酶（MAP4Ks）和双特异性磷酸酶（DUSPs）是 MAP 激酶的调节剂。几种 MAP4Ks 和 DUSPs 参与 T 细胞信号转导和自身免疫反应。HPK1（MAP4K1）、DUSP22（JKAP）和 DUSP14 是 T 细胞活化的负调节剂。一致地，SLE 患者的 T 细胞中 HPK1 和 DUSP22 的表达下调。相比之下，MAP4K3（GLK）是 T 细胞信号转导和 T 细胞介导的免疫反应的正调节剂。MAP4K3 过表达诱导的 RORγt-AhR 复合物特异性控制 T 细胞中白细胞介素 17A（IL-17A）的产生，导致自身免疫反应。一致地，SLE 患者的 T 细胞中 MAP4K3 和 RORγt-AhR 复合物以及 DUSP4 和 DUSP23 过度表达。此外，DUSPs 还参与人类自身免疫性疾病（DUSP2、DUSP7、DUSP10 和 DUSP12）或 T 细胞活化（DUSP1、DUSP5 和 DUSP14）。在这篇综述中，我们总结了 MAP4Ks 和 DUSPs，它们是 SLE 的潜在生物标志物和/或治疗靶点。
