Department of Immunology and Rheumatology and.
Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
JCI Insight. 2019 Jul 23;5(16):126457. doi: 10.1172/jci.insight.126457.
Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55ß conditioned resistance to cytokine withdrawal-induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55ß was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CTCF binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.
慢性炎症会导致系统性自身免疫性疾病患者的靶器官损伤。导致这种持久反应的因素尚未完全了解。我们分析了 PPP2R2B（B55ß）的转录调控，PPP2R2B 是一种对于免疫反应终止至关重要的分子，在自身免疫性疾病患者中进行分析。B55ß 的表达改变使自身免疫性疾病患者对细胞因子撤出诱导的死亡（CWID）具有抗性。B55ß 的上调受损是由炎症驱动的 PPP2R2B 调节元件内特定胞嘧啶的高度甲基化引起的，这阻止了 CTCF 的结合。TNF-α 可诱导健康 T 细胞中出现这种表型。我们的结果揭示了一个基因，其表达受到系统性自身免疫环境中获得性缺陷的影响，通过表观遗传机制。因为未能通过 CWID 去除激活的 T 细胞可能导致自身免疫病理学，因此该机制说明了一个恶性循环，即自身免疫炎症有助于其自身的持续存在。
