Article Text
Abstract
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.
- lupus erythematosus, systemic
- B-lymphocytes
- autoimmunity
Data availability statement
Data are available on reasonable request. All analysed sequencing datasets and open chromatin data, during the current study were deposited in the National Bioscience Database Center (NBDC) Human Database (http://humandbs.biosciencedbc.jp/) with the accession code hum0214, which can be downloaded on request. We used publicly available software for the analyses.
Statistics from Altmetric.com
Data availability statement
Data are available on reasonable request. All analysed sequencing datasets and open chromatin data, during the current study were deposited in the National Bioscience Database Center (NBDC) Human Database (http://humandbs.biosciencedbc.jp/) with the accession code hum0214, which can be downloaded on request. We used publicly available software for the analyses.
Footnotes
Handling editor Josef S Smolen
Contributors YT performed and analysed the majority of experiments in this study. YI designed the experiments, conducted analyses, as well as wrote the manuscript. MN provided in vitro support. YN made suggestions on ATAC-seq analysis. MO performed eQTL analysis. SS, TO, KI, AS and YK provided technical assistance. KY and KF supervised the project and cowrote the manuscript. KF acted as a guarantor.
Funding This study was supported by Chugai Pharmaceutical, Tokyo, Japan; the Centre of Innovation Programme from Japan Science and Technology Agency (JPMJCE1304); the Ministry of Education, Culture, Sports, and the Japan Agency for Medical Research and Development (JP17ek0109103h0003).
Competing interests YT, MO, YN and TO belong to the Social Cooperation 866 Program, Department of functional genomics and immunological diseases, supported by 867 Chugai Pharmaceutical. YN is an employee of Chugai 865 Pharmaceutical. KF receives consulting honoraria and research support from 868 Chugai Pharmaceutical.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.