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

Scott A. Jenks, Kevin S. Cashman, Esther Zumaquero, Urko M. Marigorta, Aakash V. Patel, Xiaoqian Wang, Deepak Tomar, Matthew C. Woodruff, Zoe Simon, Regina Bugrovsky, Emily L. Blalock, Christopher D. Scharer, Christopher M. Tipton, Chungwen Wei, S. Sam Lim, Michelle Petri, Timothy B. Niewold, Jennifer H. Anolik, Greg Gibson, F. Eun Hyung LeeJeremy M. Boss, Frances E. Lund, Ignacio Sanz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)725-739.e6
JournalImmunity
Volume49
Issue number4
DOIs
StatePublished - Oct 16 2018

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Keywords

  • Autoimmunity
  • CD11c
  • effector
  • human B cells
  • plasma cells
  • Systemic Lupus Erythematous
  • T-bet
  • Toll-like receptor 7
  • TRAF5

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Jenks, S. A., Cashman, K. S., Zumaquero, E., Marigorta, U. M., Patel, A. V., Wang, X., Tomar, D., Woodruff, M. C., Simon, Z., Bugrovsky, R., Blalock, E. L., Scharer, C. D., Tipton, C. M., Wei, C., Lim, S. S., Petri, M., Niewold, T. B., Anolik, J. H., Gibson, G., ... Sanz, I. (2018). Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity, 49(4), 725-739.e6. https://doi.org/10.1016/j.immuni.2018.08.015