c-Rel gain in B cells drives germinal center reactions and autoantibody production.
Autoimmune diseases
Autoimmunity
B cells
Immunology
NF-kappaB
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
23
08
2018
accepted:
11
03
2020
pubmed:
20
3
2020
medline:
3
2
2021
entrez:
20
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32191641
pii: 124382
doi: 10.1172/JCI124382
pmc: PMC7260018
doi:
pii:
Substances chimiques
Autoantibodies
0
Proto-Oncogene Proteins c-rel
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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