Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice - 19/04/17
Abstract |
Background |
The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation.
Objective |
We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice.
Methods |
Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge.
Results |
Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/− mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand–driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge.
Conclusion |
These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.
Le texte complet de cet article est disponible en PDF.Key words : Transmembrane activator and calcium modulator ligand interactor, common variable immunodeficiency, natural antibodies, pneumococcal susceptibility, B cells
Abbreviations used : APRIL, BAFF, CRD, CVID, NF-κB, NP-OVA, TACI, TD, TI, TNFR, TNP-KLH, WT
Plan
| Supported by National Institutes of Health (NIH) grants AI076210 (to R.S.G.), K08AI114968 (to E.J.), AI100114 (to R.M.), the Translational Research Program at Boston Children's Hospital (to R.M.), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program. |
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| Disclosure of potential conflict of interest: H. H. Jabara receives grant support from the National Institutes of Health (NIH). E. Janssen receives grant support from the NIH. H. Benson is an employee of Alkermes. R. Bram holds a patent on the TACI gene held by St Jude Children's Hospital and receives royalties from TACI patents. R. Malley receives grant support from the NIH, serves as a consultant for Merck, holds a patent in pneumococcal vaccines, and serves as a board member for Affinivax. R. S. Geha receives grant support from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 4
P. 1293 - avril 2017 Retour au numéro
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