Human effector B lymphocytes express ARID3a and secrete interferon alpha

Ward, Julie M.; Ratliff, Michelle; Dozmorov, Mikhail G.; Wiley, Graham B.; Guthridge, Joel M.; Gaffney, Patrick M.; James, Judith A.; Webb, Carol F.

doi:10.1016/j.jaut.2016.08.003

Cited by 32 publications

(52 citation statements)

References 49 publications

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“…Circulating ARID3a + transitional and naïve B cells from SLE patients have been shown to express high levels of IFNα (19). Comparison of type I IFN expression in freshly isolated, FACS-sorted cells from BXD2 and age-matched B6 mice revealed significantly elevated levels of endogenous type I IFN genes in T1 but not in other subsets of B cells from BXD2 mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Hamilton

Yang

et al. 2017

The Journal of Immunology

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The transitional stage of B-cell development is a formative stage in the spleen where autoreactive specificities are censored as B cells gain immune-competence, but the intrinsic and extrinsic factors regulating survival of transitional stage 1 (T1) B cells are unknown. We report that B-cell expression of IFNβ is required for optimal survival and TLR7 responses of transitional B cells in the spleen and was over-expressed in T1 B cells from BXD2 lupus-prone mice. Single-cell gene expression analysis of B6 Ifnb+/+ vs. B6 Ifnb−/− T1 B cells revealed heterogeneous expression of Ifnb in WT B cells and distinct gene expression patterns associated with endogenous IFNβ. Single cell analysis of BXD2 T1 B cells revealed that Ifnb is expressed in early T1 B-cell development with subsequent upregulation of Tlr7 and Ifna1. Together these data suggest that T1 B-cell expression of IFNβ plays a key role in regulating responsiveness to external factors.

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Section: Resultsmentioning

confidence: 99%

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

Hamilton

Yang

et al. 2017

The Journal of Immunology

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“…ARID3a has been linked to development of B-1 cells in mice, and hematopoietic stem cells from SLE patients with high levels of ARID3a in B cells when transferred to mice produced increased levels of autoantibodies (48). Moreover, innate and type I IFN pathways are markedly up-regulated in B cells with high levels of ARID3a (49). We found that ARID3a was up-regulated in BM-MSCs, and ARID3a mRNA was down-regulated in addition to IFNb mRNA when MAVS was silenced.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow–Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence‐Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein–Interferon‐β Feedback Loop

Gao

Bird

Meednu

et al. 2017

Arthritis & Rheumatology

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Objective BMSCs create a special microenvironment for hematopoiesis and immunity and also display robust immunomodulatory properties which are impaired in SLE. This study was undertaken to define the mechanisms of defects in human SLE BMSCs. Methods Patients fulfilling SLE classification criteria and healthy controls were recruited under an Institutional Review Board approved protocol (n=6 each). BMSCs were isolated with low density Ficoll/Hypaque. BMSCs were verified by flow cytometry and studied using immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay, and RNA interference. Results SLE BMSCs have a senescent phenotype characterized by reduced proliferation rate, increased production of reactive oxygen species (ROS), increased DNA damage and repair, increased expression of p53 and p16 which block the cell cycle, and altered cytokine production (increased pro-inflammatory cytokine and decreased immunomodulatory cytokine production). Moreover, SLE BMSCs have a 5 fold increase in IFNβ (p<0.05) and increased IFNβ-induced mRNAs including mRNA for the intracellular nucleic acid sensing adaptor protein MAVS whose expression was highly correlated with IFNβ levels (r > 0.9, p < 0.01). Since MAVS is known to induce IFNβ production, we hypothesized a positive feedback loop between MAVS and IFNβ. Strikingly, silencing MAVS markedly decreased IFNβ, p53, and p16 protein levels and expression of mRNAs for pro-inflammatory cytokines. Conclusions This study demonstrates a novel pathway for elevated IFNβ signaling in SLE that is not dependent on stimulation by immune complexes but rather is cell-intrinsic and critically mediated by IFNβ and MAVS, implicating new pathways as potential therapeutic targets.

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“…To unravel the mechanism behind the stimulatory effect of IFN-γ on CpG-induced IL-10, we studied the potential involvement of the type 1 IFNs IFN-α and IFN-β, since these have been described to increase TLR-induced IL-10 production in murine macrophages [64]. Interestingly, it has been reported that human B cells can produce IFN-α after stimulation with CpG class C [65]. However, while class A and class C CpG oligonucleotides are indeed potent inducers of type 1 IFNs, class B CpG (the one we used in our assays) is a weak inducer [66].…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.

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Human effector B lymphocytes express ARID3a and secrete interferon alpha

Cited by 32 publications

References 49 publications

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

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

Bone Marrow–Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence‐Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein–Interferon‐β Feedback Loop

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

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