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

Academic Article

Abstract

  • Activated naive (aNAV) B cells have been shown to be the precursor of the CD11c+T-bet+ IgD2CD272 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 (IGHD1IGHM1) 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 IgD2CD27+ cMEM B cells. The same treatment blocked the development of CD11c+Tbet+ aNAV and DN2 B cells and preserved DN B cells as CD11c2Tbet2 DN1 B cells. Lower expression of IL-4R and increased intracellular IFN-b in naive B cells was correlated with the accumulation of CD212IgD2 B cells and the development of anti-Smith and anti-DNA autoantibodies in patients with SLE (n 5 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 ISGhi SLE patients.
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    Digital Object Identifier (doi)

    Author List

  • Gao M; Liu S; Chatham WW; Mountz JD; Hsu HC
  • Start Page

  • 1513
  • End Page

  • 1522
  • Volume

  • 209
  • Issue

  • 8