Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus

• Type of Material: Article
• Authors: Scott Jenks, Emory University; Kevin S. Cashman, Emory University; Esther Zumaquero, University of Alabama Birmingham; Urko M. Marigorta, Georgia Institute of Technology; Aakash V. Patel, Emory University; Xiaoqian Wang, Emory University; Deepak Tomar, Emory University; Matthew Woodruff, Emory University; Zoe Simon, Emory University; Regina Bugrovsky, Emory University; Emily L. Blalock, Emory University; Christopher Scharer, Emory University; Christopher Tipton, Emory University; Chungwen Wei, Emory University; Sung Lim, Emory University; Michelle Petri, Johns Hopkins University; Timothy B. Niewold, New York University; Jennifer H. Anolik, University of Rochester; Ggreg Gibson, Georgia Institute of Technology; Frances Lee, Emory University; Jeremy Boss, Emory University; Frances E. Lund, University of Alabama Birmingham; Ignacio Sanz, Emory University
• Language: English
• Date: 2018-10-16
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.immuni.2018.08.015
• Title of Journal or Parent Work: Immunity
• Volume: 49
• Issue: 4
• Start Page: 725
• End Page: +
• Grant/Funding Information: This work was also supported by NIH funding: T32-DK007656 (M.C.W.), AR043737, AR069572 (The Hopkins Lupus Cohort), U19-AI110483 Autoimmunity Center of Excellence (I.S.), R37-AI049660 (I.S.), P01-AI125180 (I.S., F.E.L.), P01-AI078907 (F.L., F.E.L.), R01-AI110508 (F.L), R01-AI121252 (F.E.L.), and U19-AI109962 (F.E.L.).
• Keywords: Science & Technology; COMPARTMENT; POPULATION; T-BET; PLASMA-CELLS; IFN-GAMMA; Immunology; AUTOREACTIVITY; IDENTIFICATION; TERMINAL DIFFERENTIATION; CD11C EXPRESSION; TLR7; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Immunology

Abstract

© 2018 Elsevier Inc. Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets. The role of extrafollicular B cells in human systemic lupus is unknown. Jenks et al. define the main components of this pathway and its prominence in severe disease. Its activation is mediated by hyper-responsiveness to Toll-like receptor-7 and leads to the generation of autoreactive antibody-secreting plasmablasts.