The First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu.
Biomedical Research Support Center, Nagasaki University School of Medicine, Nagasaki, Japan.
Rheumatology (Oxford). 2022 Jul 6;61(7):3049-3059. doi: 10.1093/rheumatology/keab824.
To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology.
We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation.
The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation.
Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.
评估 B 细胞代谢功能障碍及其在系统性红斑狼疮（SLE）发病机制中的作用。
采用流式细胞术检测健康对照（HC）和 SLE 患者外周血 B 细胞代谢标志物的表达。体外分离 HC 和 SLE 患者外周 B 细胞，研究其分化过程中涉及的代谢调控机制。
SLE 患者 B 细胞中二羧酸（DiOc6）（线粒体膜超极化）的表达水平高于 HC，与 CD19+细胞中浆母细胞的百分比以及 SLEDAI（疾病活动评分）呈正相关。用 Toll 样受体 9（TLR9）配体 CpG 和 IFN-α刺激 CD19+细胞，可增强体外糖酵解、氧化磷酸化（OXPHOS）、DiOc6 表达和浆母细胞分化。在没有谷氨酰胺的情况下，糖酵解和 OXPHOS 均减少，浆母细胞分化受到抑制，而葡萄糖缺乏时则没有变化。由于谷氨酰胺是蛋白质合成的重要营养素，我们进一步研究了谷氨酰胺酶抑制剂 BPTES 的作用，该抑制剂可抑制谷氨酰胺降解。BPTES 降低了 DiOc6 表达、OXPHOS、活性氧（ROS）产生、三磷酸腺苷（ATP）产生、浆母细胞分化，而不影响糖酵解。二甲双胍抑制 CpG 和 IFN-α诱导的谷氨酰胺摄取、线粒体功能并抑制浆母细胞分化。
B 细胞中线粒体功能障碍与 SLE 中的浆母细胞分化和疾病活动相关。谷氨酰胺代谢增强的线粒体功能对浆母细胞分化至关重要，可能成为 SLE 的潜在治疗靶点。
