Date: Tuesday, November 7, 2017
Session Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis I
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Plasmacytoid dendritic cells are considered the main source of pathogenic IFN in SLE. However, recent work found that elevated serum type I IFN protein was not accompanied by increased type I IFN in circulating pDCs, suggesting the importance of other cellular sources of type I IFN in some patients. Developing transitional B cells are important targets of type I IFN in SLE, and were recently shown to produce IFNα. IFNβ expression has not been investigated in SLE B cells; in mice, however it has been identified as a prerequisite for efficient TLR stimulation, suggesting that autocrine stimulation of developing B cells with high-affinity IFNβ may be a prerequisite for subsequent immune-competence to respond to TLR challenges.
Methods: Peripheral blood mononuclear cells (PBMCs) from 34 SLE patients and 9 healthy controls were recruited; all SLE patients met the ACR 1997 revised criteria for SLE. Comprehensive clinical data was recorded for each SLE subjectin a double-blind fashion. Intracellular analysis of endogenous IFNβ was carried out using validated reagents on FACS isolated B cells.
Results: There was a significant increase in endogenous IFNβ in transitional (p = 0.002), naive (p = 0.004) and memory (p = 0.031) B cell subpopulations of SLE patients compared to healthy controls. Endogenous IFN-β in B cells was significantly higher than endogenous IFN-β in CD4 T cells, with levels equivalent to that seen in pDCs. Endogenous IFNβ was highly correlated with clinical disease including renal disease (p = 0.0072) and autoantibodies including anti-dsDNA (p = 0.036), anti-Sm (p = 0.011) and anti-SSA (p=0.04). Notably, T1/T2 B cell IFNβ expression was significantly increased in African-American patients (p=0.011) with more severe disease manifestations. T1/T2 IFNβ expression was also significantly correlated with the percent of 9G4+ autoreactive B cells (p = 0.0001) and CD19loCD38hiCD27+ plasma cell formation (p = 0.031). Upregulation of CD69 after TLR7 stimulation with CL264 was highly dependent upon B cell endogenous secretion IFNβ and could be significantly inhibited in the presence of anti-IFNβ antibody. The specific requirement for IFNβ was demonstrated by the lack of additional inhibition in the presence of anti-IFNaR neutralizing antibody, which blocks signaling from all type I IFNs. In vitro survival of purified B cells was also dependent on IFNβ after TLR7 stimulation and was significantly decreased with blockade of IFNβ.
Conclusion: Intracellular IFNβ production by early-stage transitional B cells is a novel and important B cell intrinsic factor that regulates B cell survival and sensitivity to TLR7 stimulation. B cell endogenous IFNβ may be an essential factor for their 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 provide a mechanistic basis for development of more effective therapies to dampen the type I IFN cascade by specifically targeting the high-affinity IFNβ or the enhanceosome components that promote its induction in a subgroup of lupus patients.
To cite this abstract in AMA style:Hamilton J, Wu Q, Yang P, Luo B, Liu S, Li J, Sanz I, Chatham WW, Hsu HC, Mountz JD. Interferon-β Production By B Cells Promotes B Cell Survival and Is Strongly Associated with Active Disease in African Americans with SLE [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/interferon-%ce%b2-production-by-b-cells-promotes-b-cell-survival-and-is-strongly-associated-with-active-disease-in-african-americans-with-sle/. Accessed March 27, 2023.
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