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Abstract Number: 2815

Lower IL-4R in IgD+ Naïve B Cells Is a Pre-disposing Factor for Development of T-bet+ DN2 B Cells in Systemic Lupus Erythematosus

John Mountz1, Min Gao 2, Qi Wu 3, PingAr Yang 2, Alex Essman 4, Oluwagbemiga Ojo 4, Shanrun Liu 2, Jake Chen 2, Iñaki Sanz 5, W. Winn Chatham 2 and Hui-Chen Hsu 2, 1University of Alabama at Birmingham and Birmingham VAMC, Birmingham, AL, 2University of Alabama at Birmingham, Birmingham, 3University of Alabama at Birmingham, Birmingham, AL, 4Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, 5Emory University, ATLANTA, GA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: autoantibodies, B cells, inflammatory cytokines and interferons, Systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 12, 2019

Session Title: 5T115: SLE – Etiology & Pathogenesis I: Signaling Pathways (2810–2815)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Studies to date have primarily focused on stimulators that are overexpressed and activate B cells in SLE subjects.  Factors that can maintain B cells in a resting state and may be under-expressed in SLE are largely unknown.  We utilized a combined single-cell B cell transcriptome and high dimensional flow cytometry analysis approach for a coordinated understanding of factors that are both over- and under-expressed in B-cell developmental checkpoints in SLE.

Methods: The expression of IL-4R and interferon beta (IFNβ) in subsets of B cells was analyzed using high dimensional flow cytometry analysis (n=47 patients who met the ACR classification criteria for SLE). Total B cells from 3 autoantibody (anti-DNA,,anti-Sm, and anti-histone)+ African American (AA) SLE patients, 1 autoAb(−) Europeran American (EA) SLE patient and 1 AA healthy control were purified using the StemCell Human B cell isolation kit.  A high-throughput scRNA-seq was carried out using a droplet-based 10x Chromium approach. The effects of IL-4 on IFNβ-induced IRF7 as well as on IFNɣ + a defined stimulatory media (DSM)(anti-Ig+BAFF+IL-21+TLR7+IL-2)-induced double negative 2 (DN2: CD21−CD27−IgD−CD11c+T-bet+) B cells were analyzed using an in vitro culture approach.

Results: At the protein level, within naïve (IgD+CD27−) B cells, higher expression of IFNβ and lower expression of IL-4R correlated with the percent of activated naïve CD21loIgD+ and CD21loIgD− DN B cells.  There was higher percent of IFNβ+IL-4Rlo naïve B cells in AA compared to EA SLE patients.  However, in EA, but not AA, patients, higher percent of IFNβ+IL-4Rlo naïve B cells was found in anti-Sm+ and renal disease+ patients. scRNA-seq analysis shows that the molecular signature of B cells from autoAb(+) patients is type I IFN stimulated genes (ISGs), including IRF7, ISG15, ISG20, MX1, and STAT1.  The molecular signature of B cells from autoAb(-) patients is IL4R, BACH2, S1PR1, and FCER2.  The high ISG and low IL4R was evident during the early transitional stage 1 B cells and persisted in pre-switched IGHD+ B cells.  Stimulation of B cells with DSM+IFNɣ promoted DN2 development whereas addition of IL-4 inhibited DN2 and preserved B cells at the resting naïve stage (IgD+CD11c−T-bet−). IL-4 also inhibited IFNβ-induced IRF7.

Conclusion: Down-regulation of IL-4R in naïve B cells is a major dysregulation in SLE since it may predispose SLE B cells to both type I IFN and type II IFN stimulation.  Further, lower IL-4R together with upregulation of endogenous IFNβ in naïve B cells was an important signature for activated naïve B cells.  Such signature was associated with development of DN2 B cells and, in EA patients, development of anti-Sm autoantibody. Modulation of IL-4R signaling may be developed into a novel therapy for SLE.


Disclosure: J. Mountz, VA Merit Review grant (I01BX004049), 2, Lupus Research Alliance Distinguished Innovator Award, 2, NIH R01-AI-071110, R01 AI134023, P30-AR-048311, 2; M. Gao, None; Q. Wu, None; P. Yang, None; A. Essman, None; O. Ojo, None; S. Liu, None; J. Chen, None; I. Sanz, None; W. Chatham, None; H. Hsu, Lupus Research Alliance Novel Research Award, 2.

To cite this abstract in AMA style:

Mountz J, Gao M, Wu Q, Yang P, Essman A, Ojo O, Liu S, Chen J, Sanz I, Chatham W, Hsu H. Lower IL-4R in IgD+ Naïve B Cells Is a Pre-disposing Factor for Development of T-bet+ DN2 B Cells in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/lower-il-4r-in-igd-naive-b-cells-is-a-pre-disposing-factor-for-development-of-t-bet-dn2-b-cells-in-systemic-lupus-erythematosus/. Accessed May 26, 2022.
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