Transitional B cells in quiescent SLE: An early checkpoint imprinted by IFN

J Autoimmun. 2019 Aug;102:150-158. doi: 10.1016/j.jaut.2019.05.002. Epub 2019 May 10.

Abstract

Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells.

Keywords: CD19; Interferon; Systemic lupus erythematosus; TLR9; Transitional B cells.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antigens, CD19 / biosynthesis*
  • Autoantibodies / immunology
  • B-Lymphocyte Subsets / immunology
  • Female
  • Humans
  • Interferons / immunology*
  • Lupus Erythematosus, Systemic / immunology*
  • Middle Aged
  • Precursor Cells, B-Lymphoid / immunology*
  • Toll-Like Receptor 9 / immunology*
  • Transcriptome / genetics

Substances

  • Antigens, CD19
  • Autoantibodies
  • CD19 molecule, human
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Interferons