Background Dysregulated responses to type I interferons (IFNs) is a hallmark of autoreactive B cell development in SLE patients. High sera levels of type I IFN protein were recently shown to occur in the absence of increased circulating pDCs and in the absence of increased pDC IFNs, suggesting the likelihood of other important sources of type I IFN that may act on B cells. The present study determined the cellular source of IFNβ and its association with disease activities in SLE.
Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 31 SLE patients meeting ACR 1997 revised criteria for SLE and 9 healthy controls. Intracellular IFNβ was determined using flow cytometry with FITC-anti-IFNβ mAb. Comprehensive clinical data was recorded for each SLE subject and the clinical data and laboratory analysis of B-cell intracellular IFNβ expression were collected in a double-blind fashion.
Results IFNβ was detected in various cell types including CD4 T cells, B cells and pDCs in PBMCs of SLE patients. Endogenous IFNβ in B cells was significantly higher than endogenous IFNβ in CD4 T cells and were equivalent to that seen in pDCs. Within B cells, there was a significant increase in endogenous IFNβ in all B cell subpopulations of SLE patients compared to healthy controls. The most significant increase was found in the CD27+IgD– memory subpopulation. B-cell endogenous IFNβ was not a result of B-cell uptake of exogenous IFNβ as coculture of SLE B cells with HEK293 reporter cells resulted in induction of interferon stimulatory genes as determined by the secreted alkaline phosphatase assay. This was further blocked by an anti-IFNβ neutralization antibody. Interestingly B-cell endogenous IFNβ was highly correlated with clinical disease including renal disease and autoantibodies including anti-dsDNA, anti-Sm and anti-SSA. Strikingly, the highest correlation of IFNβ with clinical manifestations was observed in African-American patients. B-cell IFNβ expression was significantly correlated with CD19loCD38hiCD27+ plasma cell formation.
Conclusion Intracellular IFNβ production by B cells is a novel and important B-cell intrinsic factor that may be essential for B-cell development into autoantibody producing B cells. The present work suggests a need for future human lupus studies into type I IFN dysregulation that pioneer beyond the view of pDC produced IFNα. These results also provided a mechanistic basis for development of more effective therapies to target the high-affinity IFNβ or the enhanceosome components that promote its induction in a subgroup of lupus patients.
Acknowledgements This work was supported by grants from R01-AI-071110, R01 AI134023, Lupus Research Alliance Distinguished Innovator Award, I01B × 004049, and 1I01B × 000600 to J.D.M, 2T32AI007051–39 Immunology T32 Training Grant and the LFA Finzi Summer Fellowship to J.A.H, and the LRA Novel Research Award to H.-C.H.
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