IL-4-Induced Quiescence of Resting Naive B Cells Is Disrupted in Systemic Lupus Erythematosus.

ABSTRACT: Activated naive (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 naive (rNAV) B cells, the transcriptomic program in naive (IGHD⁺IGHM ⁺) B cells in human healthy control subjects (HC) and subjects with 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 IFN-stimulated genes (ISGs). In HC, aNAV B cells exhibited upregulation of the gene signature of germinal center 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-β in naive B cells was correlated with the accumulation of CD21^-IgD^- B cells and the development of anti-Smith and anti-DNA autoantibodies in patients with SLE (n = 47). Our results show that IL-4R and type I IFN signaling in naive B cells induce the development of distinct lineages of cMEM versus aMEM B cells, respectively. Furthermore, diminished IL-4R signaling shifted activated B cell development from the DN1 to the DN2 trajectory in patients with SLE. Therapies that enhance IL-4R signaling may be beneficial for ISG^hi SLE patients.

SUBMITTER: Gao M 

PROVIDER: S-EPMC9741951 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature