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.
Maike Kober-Hasslacher, Hyunju Oh-Strauß, Dilip Kumar, Valeria Soberon, Carina Diehl, Maciej Lech, Thomas Engleitner, Eslam Katab, Vanesa Fernández-Sáiz, Guido Piontek, Hongwei Li, Björn Menze, Christoph Ziegenhain, Wolfgang Enard, Roland Rad, Jan P. Böttcher, Hans-Joachim Anders, Martina Rudelius, Marc Schmidt-Supprian
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.