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Abstract Number: 2814

Interferon-β Production By B Cells Promotes B Cell Survival and Is Strongly Associated with Active Disease in African Americans with SLE

Jennie Hamilton1, Qi Wu2, PingAr Yang3, Bao Luo4, Shanrun Liu5, Jun Li6, Ignacio Sanz7, W. Winn Chatham8, Hui-Chen Hsu2 and John D. Mountz9, 1Medicine/Division of Clinical Immunology and Rhematology, University of Alabama at Birmingham, Birmingham, AL, 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 3Department of Medicine, Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 4Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 5Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 6Medicine, University of Alabama at Birmingham, Birmingham, AL, 7Rheumatology and Lowance Center for Human Immunology, Emory University School of Medicine and Lowance Center for Human Immunology, Atlanta, GA, 8Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 9University of Alabama at Birmingham, Department of Medicine, Birmingham, AL

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: African-Americans, autoantibodies, Interferons and systemic lupus erythematosus (SLE)

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Session Information

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.


Disclosure: J. Hamilton, None; Q. Wu, None; P. Yang, None; B. Luo, None; S. Liu, None; J. Li, None; I. Sanz, None; W. W. Chatham, None; H. C. Hsu, None; J. D. Mountz, None.

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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