The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice.

Details

Serval ID
serval:BIB_2F6BC28E1710
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice.
Journal
Journal of Allergy and Clinical Immunology
Author(s)
Bacchelli C., Buckland K.F., Buckridge S., Salzer U., Schneider P., Thrasher A.J., Gaspar H.B.
ISSN
1097-6825 (Electronic)
ISSN-L
0091-6749
Publication state
Published
Issued date
2011
Volume
127
Number
5
Pages
1253-9.e13
Language
english
Abstract
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.
Keywords
Animals, Antibody Formation, B-Lymphocytes/immunology, B-Lymphocytes/physiology, Cell Line, Common Variable Immunodeficiency/genetics, Common Variable Immunodeficiency/immunology, Disease Models, Animal, Female, Heterozygote, Homeostasis, Homozygote, Humans, Lymphocyte Activation/immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, T-Lymphocytes/cytology, T-Lymphocytes/immunology, Transmembrane Activator and CAML Interactor Protein/genetics, Transmembrane Activator and CAML Interactor Protein/metabolism
Pubmed
Web of science
Create date
07/09/2011 10:52
Last modification date
20/08/2019 13:13
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