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c-Rel gain in B cells drives germinal center reactions and autoantibody production
- Source :
- Journal of Clinical Investigation. June, 2020, Vol. 130 Issue 6, p3270, 17 p.
- Publication Year :
- 2020
-
Abstract
- Single-nucleotide polymorphisms and locus amplification link 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.<br />Introduction c-Rel is a transcription factor of the NF-[kappa]B family strongly linked to human immune pathology. Genome-wide association studies (GWAS) demonstrate that single-nucleotide polymorphisms (SNPs) within the REL locus are [...]
- Subjects :
- Thermo Fisher Scientific Inc.
Genetic engineering -- Genetic aspects
B cells -- Genetic aspects
Autoimmunity
Autoantibodies -- Genetic aspects
Cell differentiation -- Genetic aspects
Single nucleotide polymorphisms -- Genetic aspects
Scientific equipment industry -- Genetic aspects
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 6
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.627278084
- Full Text :
- https://doi.org/10.1172/JCI124382.