GSE136035
IL-4-induced quiescence of resting naïve B cells is disrupted in systemic lupus erythematosus
Activated naïve (aNAV) B cells have been shown to be the precursor of the CD11c+T-bet+ IgD-CD27- double negative (DN)2 or atypical memory (aMEM) B cells in systemic lupus erythematosus (SLE).  To determine factors that maintain resting naïve (rNAV) B cells, the transcriptomics program in naïve (IGHD+IGHM+) B cells in human healthy controls (HC) and SLE was analyzed by single cell RNA-sequencing analysis. In HC, naive B cells expressed IL-4 pathway genes whereas in SLE, naive B cells expressed type I interferon stimulated genes (ISGs).  In HC, aNAV B cells exhibited upregulation of gene signature of germinal center (GC) and classical memory (cMEM) B cells.  In contrast, in SLE, aNAV B cells expressed signature genes of aMEM.  In vitro exposure of SLE B cells to IL-4 promoted B cell development into CD27+CD38+ plasmablasts/plasma and IgD-CD27+ cMEM B cells. The same treatment blocked the development of CD11c+Tbet+ aNAV and DN2 B cells and preserved DN B cells as CD11c-Tbet- DN1 B cells.  Lower expression of IL-4R and increased intracellular IFN-ß in naïve B cells was correlated with the accumulation of CD21-IgD- B cells and the development of anti-Smith and anti-DNA autoantibodies in SLE patients (n=47).  Our results show that IL-4R and type I IFN signaling in naïve B cells induce the development of distinct lineages of cMEM versus aMEM B cells, respectively.  Further, a diminished IL-4R signaling shifted activated B-cell development from the DN1 to the DN2 trajectory in SLE patients.   Therapies that enhance IL-4R signaling may be beneficial for ISGhi SLE. Overall design: We carried out single cell RNAseq and single-cell V(D)J seq for three autoantibody-positive (autoAb+) SLE subjects (SLEs) and Three healthy controls (HCs)