Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus
Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus
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DOI：
10.1136/annrheumdis-2021-221464
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发表时间：
2022-03-01
影响因子：
27.4
通讯作者：
Fujio, Keishi
中科院分区：
文献类型：
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作者：
Takeshima, Yusuke;Iwasaki, Yukiko;Fujio, Keishi
目的系统性红斑狼疮(SLE)是典型的系统性自身免疫性疾病。虽然长期预后有了很大改善，但更好的长期生存仍然是必要的。作为系统性红斑狼疮的一个显著特征，I型干扰素信号并不是理想的治疗靶点或结果预测指标。为了更准确地探索SLE的免疫学途径，我们对来自外周血的19个免疫细胞亚群进行了转录、表观基因组和基因组分析。方法对107例SLE患者和92例健康对照的19个免疫细胞亚群进行分类，并对其基因表达谱和基因多态性进行分析。结合差异表达基因和表达的数量性状基因座分析寻找SLE发病的关键驱动基因。结果我们发现在SLE记忆B细胞中，氧化磷酸化(OXPHOS)/线粒体功能障碍在转录、表观遗传学和遗传学上具有重要意义。特别是，我们确定OXPHOS调节基因PRDX6(过氧化还蛋白6)是SLE B细胞的关键驱动因素。Prdx6缺陷的B细胞表现出线粒体呼吸上调和抗体产生。我们发现OXPHOS信号与SLE记忆B细胞中的I型干扰素信号相关基因(ISRGs)信号有关。此外，ISRGs中与先天性免疫信号相关的基因集与OXPHOS相关，这两个特征与SLE器官损害以及特定的临床表型相关。结论本工作阐明了SLE的潜在预后指标。由于OXPHOS由电子传输链组成，这是线粒体的一个功能单位，这些发现表明线粒体功能障碍作为参与SLE的关键免疫途径的重要性。
Objective Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease. While the long-term prognosis has greatly improved, better long-term survival is still necessary. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor. To explore immunological pathways in SLE more precisely, we performed transcriptomic, epigenomic and genomic analyses using 19 immune cell subsets from peripheral blood. Methods We sorted 19 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 patients with SLE and 92 healthy controls. Combined differentially expressed genes and expression quantitative trait loci analysis was conducted to find key driver genes in SLE pathogenesis. Results We found transcriptomic, epigenetic and genetic importance of oxidative phosphorylation (OXPHOS)/mitochondrial dysfunction in SLE memory B cells. Particularly, we identified an OXPHOS-regulating gene, PRDX6 (peroxiredoxin 6), as a key driver in SLE B cells. Prdx6-deficient B cells showed upregulated mitochondrial respiration as well as antibody production. We revealed OXPHOS signature was associated with type I IFN signalling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signalling among ISRGs presented correlation with OXPHOS and these two signatures showed associations with SLE organ damage as well as specific clinical phenotypes. Conclusion This work elucidated the potential prognostic marker for SLE. Since OXPHOS consists of the electron transport chain, a functional unit in mitochondria, these findings suggest the importance of mitochondrial dysfunction as a key immunological pathway involved in SLE.