Two Lineages of Memory B Cell Development Regulated by Type I Interferon and IL-4R Are Perturbed in Systemic Lupus Erythematosus
The journal of immunology/The Journal of immunology(2021)
摘要
Abstract Abnormal expansion of type I interferon (IFN) stimulated B cells and T-bet+CD11c+IgD−CD27− DN2 atypical memory B cells are both hallmarks of SLE. To determine how they are interrelated, we have carried out single cell transcriptomics analysis using B cells derived from 3 SLE patients (anti-DNA+ and anti-Smith+) and 3 healthy controls (HCs)(all African Americans). We have identified that elevation of IL4R in pre-switched IGHM+/IGHD+ B cells is the opposing signature of type I IFN stimulated genes (ISGs) and DN2 B cells (TBX21, ITGAX, FCRL3, FCRL5, and ZEB2). In HCs, IGHM+/IGHD+ B cells expressed elevated IL4R. Further, activated naïve B cells (IGHM+IGHD+IGHG+) exhibited upregulation of the germinal center-oriented classical memory B-cell signature genes, CD27, TNFRSF13B (the gene encoding TACI), and GPR183 (the gene encoding EBI2). Flow cytometry analysis confirmed that down-regulation IL-4R and upregulation of intracellular IFN-β in naïve IgD+CD27− B cells correlated with the accumulation of atypical CD21−IgD−CD27−B cells and a reduction in the percentage of classical IgD−CD27+memoryB cells in SLE patients (n=47). In vitro exposure of SLE B cells to IL-4 prior to treatment with anti-Ig+IL-21+IFN-gamma+TLR7+BAFF stimulation significantly enhanced B-cell development into CD27+CD38+ plasmablasts/plasma cells as well as IgD−CD27+memoryB cells but it significantly blocked the development of DN2 B cells. Our results show that upregulation of type I IFN and down-regulation of IL-4R signaling in naïve B cells lead to the accumulation of atypical memory B cells in SLE. Type I IFN and IL-4R signaling in naïve B cells induce the development of distinct lineages of atypical versus classical memory B cells, respectively.
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