BOB.1 controls memory B-cell fate in the germinal center reaction

J Autoimmun. 2019 Jul;101:131-144. doi: 10.1016/j.jaut.2019.04.011. Epub 2019 Apr 30.

Abstract

During T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical autoimmune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination.

Keywords: Autoimmune disease; B cell; BOB.1; Germinal center; Memory B cell; Rheumatoid arthritis.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Biomarkers
  • Cell Line
  • Gene Expression
  • Germinal Center / immunology*
  • Germinal Center / metabolism*
  • Humans
  • Immunologic Memory / genetics*
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Mice
  • Mice, Knockout
  • Plasma Cells / immunology
  • Plasma Cells / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Rheumatic Fever / genetics
  • Rheumatic Fever / immunology
  • Rheumatic Fever / metabolism
  • Rheumatic Fever / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Trans-Activators / genetics*

Substances

  • Biomarkers
  • POU2AF1 protein, human
  • Receptors, Antigen, B-Cell
  • Trans-Activators