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Kober-Hasslacher, Maike; Oh-Strauss, Hyunju; Kumar, Dilip; Soberon, Valeria; Diehl, Carina; Lech, Maciej; Engleitner, Thomas; Katab, Eslam; Fernandez-Saiz, Jvanesa; Piontek, Guido; Li, Hongwei; Menze, Bjorn; Ziegenhain, Christoph; Enard, Wolfgang; Rad, Roland; Boettcher, Jan P.; Anders, Hans-Joachim; Rudelius, Martina and Schmidt-Supprian, Marc (2020): c-Rel gain in B cells drives germinal center reactions and autoantibody production. In: Journal of Clinical Investigation, Vol. 130, No. 6: pp. 3270-3286

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Single-nucleotide polymorphisms and locus amplification fink the NF-kappa B 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.

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