B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells

Cell Rep. 2018 Jul 10;24(2):406-418. doi: 10.1016/j.celrep.2018.06.046.

Abstract

Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways. Through bone marrow chimeras, DNA-reactive B cell transfer, and GC-specific Cre mice, we confirm that IFNαR signaling in B cells promotes autoreactive B cell development into both pathways. Transcriptomic analysis reveals gene expression alterations in multiple signaling pathways in non-GC and GC B cells in the absence of IFNαR. Finally, we find that T1IFN signaling promotes autoreactive B cell development in the AFC and GC pathways by regulating BCR signaling. These data suggest value for anti-IFNαR therapy in individuals with elevated T1IFN activity before clinical disease onset.

Keywords: B cell tolerance; B cells; antibody-forming cells; autoimmunity; spontaneous germinal centers; systemic lupus erythematosus; type 1 interferon signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Antinuclear / metabolism
  • Antibody Affinity
  • Antibody Formation
  • Antigens / metabolism
  • Autoantibodies / biosynthesis
  • B-Lymphocytes / immunology*
  • DNA / metabolism
  • Female
  • Germinal Center / metabolism
  • Immune Tolerance*
  • Immunization
  • Interferon Type I / metabolism*
  • Mice, Inbred C57BL
  • Receptor, Interferon alpha-beta / metabolism
  • Signal Transduction*
  • Transcriptome / genetics

Substances

  • Antibodies, Antinuclear
  • Antigens
  • Autoantibodies
  • Ifnar1 protein, mouse
  • Interferon Type I
  • Receptor, Interferon alpha-beta
  • DNA