title: Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity.
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.
authors.affiliation: CNRS UPR9021, IBMC, Strasbourg, France.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pasquali
authors.forename: Anne
authors.initials: A
authors.lastname: Soley
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Knapp
authors.forename: Marion
authors.initials: M
authors.lastname: Decossas
authors.forename: Aurélie
authors.initials: A
authors.lastname: Kern
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Fauny
authors.forename: Luc
authors.initials: L
authors.lastname: Marcellin
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Korganow
authors.forename: Thierry
authors.initials: T
authors.lastname: Martin
authors.forename: Pauline
authors.initials: P
authors.lastname: Soulas-Sprauel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D004247:DNA / Q000378:metabolism; D020690:GTPase-Activating Proteins; D006801:Humans; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D011446:Prospective Studies; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D011947:Receptors, Antigen, B-Cell; C517115:TBC1D10C protein, human; C580816:TBC1D10C protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA