Abstract
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.
Highlights
Both genetic and environmental factors contribute to the clinical heterogeneity of autoimmune diseases [1,2]
We summarize the potential utilization of MAP4Ks and dual-specificity phosphatases (DUSPs) in T cells as biomarkers and/or therapeutic targets for Systemic lupus erythematosus (SLE) (Figure 1)
GCK-Like Kinase (GLK) is overexpressed in the peripheral blood leukocytes (PBLs) of SLE patients; the activation of PKCθ and IKK are concomitantly induced in SLE PBLs compared to those of healthy controls [22] (Figure 2)
Summary
Both genetic and environmental factors contribute to the clinical heterogeneity of autoimmune diseases [1,2]. Signaling molecules (e.g., kinases and phosphatases) of immune cells play important roles in immune responses and autoimmune pathogenesis through induction of cytokines or chemokines [20,21,22,23,24]. Signaling molecules in T cells are either potential biomarkers or therapeutic targets in the treatment of autoimmune diseases. Mitogen-activated protein kinases (MAPKs) are involved in the pathogenesis of autoimmune diseases, including SLE [25]; MAPK inhibitors have been developed for the attenuation of autoimmune responses [20,26]. We summarize the potential utilization of MAP4Ks and DUSPs in T cells as biomarkers and/or therapeutic targets for SLE (Figure 1). DNA hypermethylation on the HGK promoter results in HGK downregulation and TRAF2 overexpression in T cells of human non-obese type II diabetes patients.
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