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

Immunity. 2018 Oct 16;49(4):725-739.e6. doi: 10.1016/j.immuni.2018.08.015. Epub 2018 Oct 9.


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.

Keywords: Autoimmunity; CD11c; Systemic Lupus Erythematous; T-bet; TRAF5; Toll-like receptor 7; effector; human B cells; plasma cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Female
  • Gene Regulatory Networks / genetics
  • Gene Regulatory Networks / immunology
  • Humans
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Male
  • Middle Aged
  • Plasma Cells / immunology
  • Plasma Cells / metabolism
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology*
  • Toll-Like Receptor 7 / metabolism
  • Transcriptome / genetics
  • Transcriptome / immunology
  • Young Adult


  • Toll-Like Receptor 7