Carabin deficiency in B cells increases BCR‐TLR9 costimulation‐induced autoimmunity
Open Access
- 29 October 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 4 (12), 1261-1275
- https://doi.org/10.1002/emmm.201201595
Abstract
The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB × NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock‐out and B‐cell‐conditional knock‐out murine models, we identify Carabin as a new negative regulator of B‐cell function, whose deficiency in B cells speeds up early B‐cell responses and makes the mice more susceptible to anti‐dsDNA production and renal lupus flare after stimulation with a Toll‐like Receptor 9 agonist, CpG‐DNA. Finally, in vitro analysis of NFκB activation and Erk phosphorylation in TLR9‐ and B‐cell receptor (BCR)‐stimulated Carabin‐deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self‐reactive B cells.Keywords
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