Perez-Bercoff Danielle, Laude Hélène, Lemaire Morgane, Hunewald Oliver, Thiers Valérie, Vignuzzi Marco, Blanc Hervé, Poli Aurélie, Amoura Zahir, Caval Vincent, Suspène Rodolphe, Hafezi François, Mathian Alexis, Vartanian Jean-Pierre, Wain-Hobson Simon
Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, 4354, Esch-sur-Alzette, Luxembourg.
ICAReB Platform, 28 rue du Docteur Roux, 75724, Paris Cedex 15, France.
Sci Rep. 2021 Apr 12;11(1):7893. doi: 10.1038/s41598-021-87024-1.
APOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.
载脂蛋白B mRNA编辑酶催化多肽样3（A3）酶最为人所知的是其作为抗病毒限制因子和癌症诱变剂的作用。尽管其中四种，即A3A、A3B、A3F和A3G，由I型干扰素（IFN-I）诱导产生，但其在炎症状态中的作用尚不清楚。因此，我们研究了A3，特别是A3A和A3B（因其能够编辑细胞DNA）在系统性红斑狼疮（SLE）中的表达，SLE是一种以血清IFN-α水平升高为特征的慢性炎症性疾病。在一组57例SLE患者中，与健康对照相比，A3A和A3B以及A3C和A3G上调了约10至15倍（A3B超过1000倍），特别是在病情发作且血清IFN-α水平升高的患者中。羟氯喹、皮质类固醇和免疫抑制治疗并未使A3水平逆转。在14.9%的患者和10%的对照中检测到增强A3A的A3AΔ3B多态性，其与更高的A3A mRNA表达相关。A3A和A3B mRNA水平与双链DNA断裂呈正相关，与淋巴细胞减少呈负相关，但A3C或A3G并非如此。在培养中，将SLE患者外周血单个核细胞（PBMC）暴露于IFN-α 4小时可诱导大量且持续的A3A水平，并导致大量细胞死亡。此外，端粒酶逆转录酶（TERT）启动子中的rs2853669 A>G多态性破坏了一个Ets-TCF结合位点并影响某些癌症，在SLE患者中高度普遍，可能导致淋巴细胞减少。综上所述，这些发现表明，高基线A3A和A3B水平可能导致SLE患者的细胞脆弱、淋巴细胞减少和新抗原的产生。靶向A3表达可能是逆转细胞死亡和新抗原产生的一种策略。
