PT - JOURNAL ARTICLE AU - Yusuke Takeshima AU - Yukiko Iwasaki AU - Masahiro Nakano AU - Yuta Narushima AU - Mineto Ota AU - Yasuo Nagafuchi AU - Shuji Sumitomo AU - Tomohisa Okamura AU - Keith B Elkon AU - Kazuyoshi Ishigaki AU - Akari Suzuki AU - Yuta Kochi AU - Kazuhiko Yamamoto AU - Keishi Fujio TI - Immune cell multi-omics analysis reveals contribution of oxidative phosphorylation to B cell functions and organ damage of lupus AID - 10.1101/2021.10.08.463629 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.10.08.463629 4099 - http://biorxiv.org/content/early/2021/10/09/2021.10.08.463629.short 4100 - http://biorxiv.org/content/early/2021/10/09/2021.10.08.463629.full AB - Objective Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, with a poor long-term prognosis. 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 integrative analysis of transcriptomics, epigenomics, and genomics using each immune cell subset from peripheral blood.Methods We sorted 18 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 SLE patients and 92 healthy controls. Open chromatin information was also taken by ATAC-seq analysis. Combined differentially expressed genes (DEGs) and expression quantitative trait loci (eQTL) 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, 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 signaling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signaling 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.Competing Interest StatementY.T., M.O., Y.N. and T.O. belong to the Social Cooperation Program, Department of functional genomics and immunological diseases, supported by Chugai Pharmaceutical. Y.N. is an employee of Chugai Pharmaceutical. K.F. receives consulting honoraria and research support from Chugai Pharmaceutical.