c-Rel gain in B cells drives germinal center reactions and autoantibody production

J Clin Invest. 2020 Jun 1;130(6):3270-3286. doi: 10.1172/JCI124382.


Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.

Keywords: Autoimmune diseases; Autoimmunity; B cells; Immunology; NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation*
  • Autoantibodies / genetics
  • Autoantibodies / immunology*
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Mice
  • Mice, Transgenic
  • Plasma Cells / immunology*
  • Plasma Cells / pathology
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / immunology*


  • Autoantibodies
  • Proto-Oncogene Proteins c-rel