Transcriptomics

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C-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice


ABSTRACT: 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 overexpress c- Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictate expansion of germinal center (GC) B cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescues terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GC B cells transcription-independent regulation produces the highest c-Rel protein levels amongst B cell subsets. In c-Rel overexpressing GC B cells this causes enhanced nuclear translocation, a profoundly altered transcriptional program and increased proliferation. Finally, we provide the first link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells causes autoantibody production and renal immune complex deposition.

ORGANISM(S): Mus musculus

PROVIDER: GSE143156 | GEO | 2020/06/04

REPOSITORIES: GEO

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