The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency - 07/08/11
Reprint requests: Raif S. Geha, MD, Division of Immunology, Children’s Hospital Boston, 1 Blackfan Circle, Karp 10, Boston, MA 02115.Abstract |
Background |
TNFRSF13B, which encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), is mutated in 10% of patients with common variable immunodeficiency. One of the 2 most common TACI mutations in common variable immunodeficiency, C104R, abolishes ligand binding and is found predominantly in the heterozygous state. The murine TACI mutant C76R is the equivalent of the human TACI mutant C104R.
Objective |
We sought to define the consequence of the C76R mutation on TACI function in mice that express both wild-type TACI and the murine C76R mutant.
Methods |
Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI+/− B6/129 background (C76R/TACI+/− mice) were constructed. Serum immunoglobulins and antibody responses to the type II T-independent antigen trinitrophenylated (TNP)-Ficoll were determined by means of ELISA. B-cell proliferation in response to a proliferation-inducing ligand was determined based on tritiated thymidine incorporation into DNA. IgG1 secretion by B cells in response to a proliferation-inducing ligand plus IL-4 was determined by means of ELISA.
Results |
C76R/TACI+/− mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI+/+ B6/129 control animals, and their B cells were impaired in their capacity to proliferate and secrete IgG1 in response to TACI ligation. Unexpectedly, TACI+/− mice had similarly impaired B-cell function as C76R/TACI+/− littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI+/− mice on the C57BL/6 background.
Conclusion |
These results suggest that the human TACI mutant C104R might impair TACI function in heterozygotes through haploinsufficiency.
Le texte complet de cet article est disponible en PDF.Key words : Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), common variable immunodeficiency, a proliferation-inducing ligand (APRIL), haploinsufficiency, murine model
Abbreviations used : APRIL, BAFF, CRD, CVID, KLH, MFI, TACI, TLR, TNP, WT
Plan
| Supported by National Institute of Health grants AI-031541 and T32-AI-007512; the American Academy of Allergy, Asthma & Immunology GSK Award (J.J.L.); and the Austrian Science FundJ2744-B12 (I.R.). |
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| Disclosure of potential conflict of interest: S. R. Dillon is an employee and stockholder of ZymoGenetics, Inc. R. Bram has received payment from St Jude Children’s Hospital and ZymoGenetics for patents related to the TACI gene. R. S. Geha has received research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest. |
Vol 126 - N° 6
P. 1234 - décembre 2010 Retour au numéro
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