Single-Cell Transcriptomic and Metabolic Signatures in Exhausted and Classical Memory B Cells—An Exploratory Analysis in Systemic Lupus Erythematosus and Lupus Nephritis

Aim: Disturbances in exhausted and classical memory B cells have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN), but the genetic regulation of their homeostasis remains poorly understood. Methods: We analyzed the single-cell RNA-seq data of peripheral blood mononuclear cells (PBMCs) from the NIH SLE dataset (GSE135779) and another published LN single-cell RNA-seq dataset (dbGAP database accession code phs001457.v1.p1). Overlapping differentially expressed genes (DEGs) in exhausted and classical memory B cells from SLE and LN patients were identified, and their altered expression was validated in B cells obtained from LN patients. GO and KEGG analyses were used to analyze associated pathways. The relationships between exhausted and classical memory B cells and cellular metabolic pathways were also assessed. Results: Three DEGs (IFI44L, XAF1, and MX1) were detected in both exhausted and classical memory B cells, and their increased expression was verified in classical and exhausted memory B cells obtained from LN patients during remission. The protein–protein interaction network of the DEGs suggested that STAT1 showed the highest eigenvector centrality for these DEGs. IFI44L, XAF1 and MX1 were involved in distinct biological processes and immune pathways (especially JAK-STAT). Classical memory B cells showed higher expression of genes involved in sulfur metabolism (SQRDL and TST), amino sugar metabolism (GFPT1 and UAP1), and butanoate metabolism (ACADS and ACAT1), while exhausted B cells exhibited inverse relationships with these metabolic pathways. Conclusions: Altered expression of IFI44L, XAF1 and MX1 is associated with distinct metabolic signatures and immune pathways in exhausted and classical memory B cells in SLE and LN.