Carabin deficiency in B cells increases BCR‐TLR9 costimulation‐induced autoimmunity

EMBO Molecular Medicine

Jean-Nicolas Schickel²  Jean-Louis Pasquali²  Anne Soley²  Anne-Marie Knapp²  Marion Decossas²  Aurélie Kern¹  Jean-Daniel Fauny²  Luc Marcellin³  Anne-Sophie Korganow²  Thierry Martin² 

[1] EA4438, Groupe Borréliose de Lyme, UFR Sciences Pharmaceutiques and UFR Médecine, Université de Strasbourg, Strasbourg, France;CNRS UPR9021, IBMC, Strasbourg, France;Department of Anatomopathology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

关键词: autoimmunity;    B cells;    Carabin;    mouse models;    systemic lupus erythematosus;   

DOI  :  10.1002/emmm.201201595

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.