Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice

Haifa H. Jabara, John J. Lee, Erin Janssen, Sumana Ullas, Kyriaki Liadaki, Lilit Garibyan, Halli Benson, Tatyana Sannikova, Richard J Bram, Lennart Hammarstrom, Anthony C. Cruz, Richard Siegel, John Manis, Richard Malley, Raif S. Geha

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Jan 8 2016

Fingerprint

Haploinsufficiency
Ligands
Calcium
B-Lymphocytes
Antibody Formation
Phosphorylcholine
Blood Donors
Mutation
Activator Appliances
Immunoglobulin Class Switching
Pneumococcal Infections
HEK293 Cells
Mutant Proteins
Luciferases

Keywords

  • B cells
  • Common variable immunodeficiency
  • Natural antibodies
  • Pneumococcal susceptibility
  • Transmembrane activator and calcium modulator ligand interactor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice. / Jabara, Haifa H.; Lee, John J.; Janssen, Erin; Ullas, Sumana; Liadaki, Kyriaki; Garibyan, Lilit; Benson, Halli; Sannikova, Tatyana; Bram, Richard J; Hammarstrom, Lennart; Cruz, Anthony C.; Siegel, Richard; Manis, John; Malley, Richard; Geha, Raif S.

In: Journal of Allergy and Clinical Immunology, 08.01.2016.

Research output: Contribution to journalArticle

Jabara, HH, Lee, JJ, Janssen, E, Ullas, S, Liadaki, K, Garibyan, L, Benson, H, Sannikova, T, Bram, RJ, Hammarstrom, L, Cruz, AC, Siegel, R, Manis, J, Malley, R & Geha, RS 2016, 'Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.07.028
Jabara, Haifa H. ; Lee, John J. ; Janssen, Erin ; Ullas, Sumana ; Liadaki, Kyriaki ; Garibyan, Lilit ; Benson, Halli ; Sannikova, Tatyana ; Bram, Richard J ; Hammarstrom, Lennart ; Cruz, Anthony C. ; Siegel, Richard ; Manis, John ; Malley, Richard ; Geha, Raif S. / Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice. In: Journal of Allergy and Clinical Immunology. 2016.
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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.",
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AU - Jabara, Haifa H.

AU - Lee, John J.

AU - Janssen, Erin

AU - Ullas, Sumana

AU - Liadaki, Kyriaki

AU - Garibyan, Lilit

AU - Benson, Halli

AU - Sannikova, Tatyana

AU - Bram, Richard J

AU - Hammarstrom, Lennart

AU - Cruz, Anthony C.

AU - Siegel, Richard

AU - Manis, John

AU - Malley, Richard

AU - Geha, Raif S.

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N2 - 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.

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KW - Natural antibodies

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