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

Kober-Hasslacher, M., Oh-Strauss, H., Kumar, D., Soberon, V., Diehl, C., Lech, M., Engleitner, T., Katab, E., Fernandez-Saiz, V., Piontek, G., Li, H. W., Menze, B., Ziegenhain, C., Enard, W., Rad, R., Bottcher, J. P., Anders, H. J., Rudelius, M., Schmidt-Supprian, M. (2020). J Clin Invest 130, 3270-3286.

DOI:10.1172/Jci124382(link is external)


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.