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Abstract Number: 1088

Expansion of Transitional B Cells in SLE Patients Correlates with Increased Toll-like Receptor 7 Expression

Ting Wang1,2, John Marken1, Karen Cerosaletti3 and Natalia V. Giltiay1, 1Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA, Seattle, WA, 2Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China, Beijing, China, 3Translational Research Program Benaroya Research Institute at Virginia Mason, Seattle, WA, USA, Seattle, WA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: B cells, SLE and autoantibodies

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Session Information

Date: Monday, November 14, 2016

Session Title: B Cell Biology and Targets in Autoimmune Disease - Poster I: SLE and Sjögren's

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  B cell hyperactivation and autoantibody (auto-Ab) production are hallmarks of SLE. Auto-Abs, reactive to RNA-containing antigens are found in a fraction of SLE patients, particularly those with severe disease activity. Toll-like receptor 7 (TLR7), an intracellular TLR that recognizes ssRNA, has been highly implicated in the generation of pathogenic anti-RNA autoantibodies in SLE, however the cellular origin of anti-RNA Ab–secreting cells is not well defined. Human transitional (TR) B cells have been previously shown to be enriched in polyreactive specificities and increase of TR B cells have been described in SLE patients. This study was undertaken to determine a possible link between the transitional B cell expansion and increase in TLR7 expression in SLE.

Methods: Human peripheral blood mononuclear cells (PBMCs) were collected from both SLE patients and healthy donors (HDs) and analyzed by multicolor flow cytometry. Frequencies of TR B cells within the CD19+ cell population were determined based on the relative expression of IgD, CD10, CD24, CD27, and CD38 surface markers. Expression levels of TLR7 and TLR9 were measured by real-time PCR. Additionally, CD19+ CD38++CD24++ TR B cells from human cord blood were isolated by cell sorting. These cells were stimulated with IFNα, followed by stimulation with anti-IgM and/or TLR7 agonist R848. Changes in mRNA levels of TLR7 were analyzed 3-6 hours post-stimulation. Plasma cell differentiation was assessed by flow cytometry after 5 days of in vitro cell culture; antibody production was analyzed by ELISA, and the expression of cytokines was measured by bead-based immunoassay.

Results:  Analysis of the B cell compartment revealed a significant increase in the frequencies of circulating CD19+CD27–IgD+CD10+CD38++CD24++ TR B cells in SLE patients, compared to HDs. We found a significant positive correlation between the levels of TLR7, but not TLR9 expression, and the frequencies of circulating TR B cells. SLE patients who carry a risk G allele (TLR7 polymorphism rs3853839, associated with increased TLR7 expression) show a trend toward increased TR cell frequencies compared to non-risk allele carriers. SLE patients with high frequencies of TR B cells were also more likely to been found positive for pathogenic Sm/RNP auto-Abs in the clinic. IFNα treatment induced a nearly 10-fold increase in the expression of TLR7 and IRF7 in TR B cells isolated from umbilical cord blood. IFNα-primed TR B cells become highly responsive to in vitro stimulation with R848 and differentiated into CD27++CD38++CD24–plasmablast in the absence of any other stimuli. Stimulation of TR B cells with R848 promoted IgM production, whereas stimulation with anti-IgM plus R848 induced IFN-γ, IL-6 and IL-10 cytokines.

Conclusion: Our findings show a direct correlation between TLR7 expression levels and the expansion of TR B cells in SLE patients. Upon IFNα exposure, human TR B cells become hyper-responsive to stimulation through TLR7. Our study suggest that human TR B cells might be an important source of auto-Abs and provide a new link between innate IFN and TLR7 signaling and B cell activation in SLE.


Disclosure: T. Wang, None; J. Marken, None; K. Cerosaletti, None; N. V. Giltiay, None.

To cite this abstract in AMA style:

Wang T, Marken J, Cerosaletti K, Giltiay NV. Expansion of Transitional B Cells in SLE Patients Correlates with Increased Toll-like Receptor 7 Expression [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/expansion-of-transitional-b-cells-in-sle-patients-correlates-with-increased-toll-like-receptor-7-expression/. Accessed March 1, 2021.
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