Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
Clin Immunol. 2018 Jan;186:38-42. doi: 10.1016/j.clim.2017.07.012. Epub 2017 Jul 21.
Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute to human and murine lupus immunopathology. PP2A expression in SLE is controlled both epigenetically and genetically, and it is increased in patients with SLE, which contributes to decreased IL-2 production, decreased CD3ζ and increased FcRγ expression on the surface of T cells, increased CREMα expression, hypomethylation of genes associated with SLE pathogenesis, and increased IL-17 production. β regulatory subunit of PP2A regulates IL-2 deprivation-induced T cell death and is decreased in SLE patients. A mouse overexpressing PP2A in T cells displays peripheral granulocytosis, elevated IL-17 production, and develops glomerulonephritis when challenged. A mouse which lacks PP2A only in regulatory T cells develops severe autoimmunity and multiorgan inflammation because of loss of restraint on mTORC1 and inability of Foxp3+ cells to regulate conventional T cells. Targeting PP2A in T cell subsets may be therapeutic for SLE and other autoimmune diseases.
蛋白磷酸酶 2A（PP2A）是第一个被认为有助于人类和鼠狼疮免疫病理学的丝氨酸/苏氨酸磷酸酶。SLE 中的 PP2A 表达受到表观遗传和遗传控制，在 SLE 患者中增加，导致 IL-2 产生减少、CD3ζ 减少和 T 细胞表面 FcRγ 表达增加、CREMα 表达增加、与 SLE 发病机制相关的基因去甲基化增加和 IL-17 产生增加。PP2A 的β调节亚基调节 IL-2 剥夺诱导的 T 细胞死亡，在 SLE 患者中减少。在 T 细胞中过表达 PP2A 的小鼠显示外周粒细胞增多、IL-17 产生增加，并在受到挑战时发展为肾小球肾炎。仅在调节性 T 细胞中缺乏 PP2A 的小鼠由于 mTORC1 的约束丧失以及 Foxp3+细胞无法调节常规 T 细胞而发展为严重的自身免疫和多器官炎症。针对 T 细胞亚群中的 PP2A 可能对 SLE 和其他自身免疫性疾病具有治疗作用。
