Cutting Edge: Endogenous IFN-β Regulates Survival and Development of Transitional B Cells

Hamilton, Jennie A; Wu, Qi; Yang, PingAr; Luo, Bao; Liu, Shanrun; Hong, Huixian; Li, Jun; Walter, Mark R.; Fish, Eleanor N.; Hsu, Hui‐Chen; Mountz, John D.

doi:10.4049/jimmunol.1700888

Cited by 29 publications

(43 citation statements)

References 26 publications

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“…However, the earliest IgM hi IgD lo T1 B-cell stage manifests low BAFF responsiveness, and BCR-and BAFF-mediated signals are not well-integrated at this stage. 61,62 Spleen T1 B cells in contrast express low levels of BAFF-R and are neither expanded in BAFF transgenic mice nor in mice-administered exogenous BAFF. 60,61 It remains unclear whether BAFF promotes T1 progression to the T2 stage in vivo.…”

Section: T1 B-cell Regulation By Autocrine/ Paracrine Ifnβmentioning

confidence: 99%

“…61 cells from SLE patients. In contrast to BAFF-R, IFNAR1 is highly expressed on both T1 and T2 B cells and is downregulated on mature B cells.…”

Section: T1 B-cell Regulation By Autocrine/ Paracrine Ifnβmentioning

confidence: 99%

“…61,78 Intracellular nucleic acid sensors are important in the pathogenesis of SLE, and TLR7 in particular is associated with the development of antibodies targeting RNA-associated antigens in SLE. 61,78 Intracellular nucleic acid sensors are important in the pathogenesis of SLE, and TLR7 in particular is associated with the development of antibodies targeting RNA-associated antigens in SLE.…”

Section: The Ifnβ-tlr7-ifnα Loop Of Autoreactive Bcell Developmentmentioning

confidence: 99%

“…2,140,153,154 Because of their advantageous anatomic location of MZMs, they act as the final follicular AC-Ag exclusion barrier. 20,61,78,80,81,[155][156][157] In SLE, such clearance mechanisms can lead to the localization of apoptotic cell debris in the endosome and induction of type l interferons via stimulation through the endosomal TLRs including TLR7 and TLR9. One of the most fundamental observations in SLE is the increased circulation of apoptotic cell debris.…”

Section: Breakdown Of the Mzm Follicular Exclusion Barrier In Slementioning

confidence: 99%

“…T2 progression 61. This is reminiscent of the priming role that IFNβ can elicit in other cell types, whereby low levels of IFNβ leads to the accumulation of antiviral factors enabling rapid amplification of subsequent antiviral responses 64.…”

mentioning

confidence: 99%

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Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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Autoreactive B-cell development in SLE (systemic lupus erythematosus) is often considered in terms of the extrinsic stimuli and factors that drive B cells into autoantibody production. This review focuses on the novel concept that autoreactive B cells are initially programmed at the transitional stage for heightened susceptibility for development into autoantibody secreting plasmablasts (Figure 1). During peripheral B-cell development in the spleen, transitional B-cells expressing elevated levels of endogenous intracellular interferon-β (IFNβ) exhibit enhanced survival and activation through the B-cell receptor (BCR), a feature associated with more active SLE, particularly in African American (AA) patients. 1 Following passage through the transitional stage, a second major defect is the failure of B cells to maintain the integrity of tolerogenic splenic marginal zone macrophages (MZM), which normally function to remove apoptotic cell debris in a non-inflammatory fashion through upregulation of indoleamine-pyrrole 2,3-dioxygenase (IDO). 2 This failure is amplified by the type I IFN-driven migratory properties of marginal zone-precursor (MZ-P) B cells as they lose their tethering to sphingosine-1-phosphate (S1P) and drift across the follicular exclusion barrier. 3-8 Here they act as potent antigen-carrying, co-stimulatory cells expressing inflammatory cytokine IL-6 and low levels of the antiinflammatory cytokine IL-10. 9 In addition, Ag transporting MZ-P B-cells Abstract The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B-cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B-cells encounter T-follicular helper cells (Tfh) that produce interleukin (IL)-21, IL-4 and pathogenic cytokines, IL-17 and IFN gamma (IFNɣ). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B-cell stage as a major juncture where transient autocrine IFNβ expression by developing B-cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody-producing plasmablasts. Recent studies highlight transitional B-cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B-cell responsiveness to cytokines and other environment factors.

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