Titre
The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Bacchelli, C.
Auteure/Auteur
Buckland, K.F.
Auteure/Auteur
Buckridge, S.
Auteure/Auteur
Salzer, U.
Auteure/Auteur
Schneider, P.
Auteure/Auteur
Thrasher, A.J.
Auteure/Auteur
Gaspar, H.B.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1097-6825
Statut éditorial
Publié
Date de publication
2011
Volume
127
Numéro
5
Première page
1253
Dernière page/numéro d’article
9.e13
Langue
anglais
Résumé
BackgroundMutations in TNFRSF13B, the gene encoding transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), are found in 10% of patients with common variable immunodeficiency. However, the most commonly detected mutation is the heterozygous change C104R, which is also found in 0.5% to 1% of healthy subjects. The contribution of the C104R mutation to the B-cell defects observed in patients with common variable immunodeficiency therefore remains unclear.ObjectiveWe sought to define the functional consequences of the C104R mutation on B-cell function.MethodsWe performed in vitro studies of TACI C104R expression and signaling. A knock-in mouse with the equivalent mutation murine TACI (mTACI) C76R was generated as a physiologically relevant model of human disease. We examined homozygous and heterozygous C76R mutant mice alongside wild-type littermates and studied specific B-cell lineages and antibody responses to T cell-independent and T cell-dependent challenge.ResultsC104R expression and ligand binding are significantly diminished when the mutant protein is expressed in 293T cells or in patients' cell lines. This leads to defective nuclear factor κB activation, which is proportionally restored by reintroduction of wild-type TACI. Mice heterozygous and homozygous for mTACI C76R exhibit significant B-cell dysfunction with splenomegaly, marginal zone B-cell expansion, diminished immunoglobulin production and serological responses to T cell-independent antigen, and abnormal immunoglobulin synthesis.ConclusionsThese data show that the C104R mutation and its murine equivalent, C76R, can significantly disrupt TACI function, probably through haploinsufficiency. Furthermore, the heterozygous C76R mutation alone is sufficient to disturb B-cell function with lymphoproliferation and immunoglobulin production defects.
Sujets
PID Serval
serval:BIB_2F6BC28E1710
PMID
Date de création
2011-09-07T09:52:36.976Z
Date de création dans IRIS
2025-05-20T16:29:28Z
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Nom
128. Baccheli et al.pdf
Version du manuscrit
preprint
Taille
3.31 MB
Format
Adobe PDF
PID Serval
serval:BIB_2F6BC28E1710.P001
URN
urn:nbn:ch:serval-BIB_2F6BC28E17106
Somme de contrôle
(MD5):7964dc24703e793bbee706e543f2256b