The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency

John J. Lee, Haifa H. Jabara, Lilit Garibyan, Ingrid Rauter, Tatyana Sannikova, Stacey R. Dillon, Richard J Bram, Raif S. Geha

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume126
Issue number6
DOIs
StatePublished - Dec 2010

Fingerprint

Activator Appliances
Cyclophilins
Haploinsufficiency
B-Lymphocytes
T Independent Antigens
Common Variable Immunodeficiency
Ligands
Calcium
Ficoll
Antibody Formation
Immunoglobulin G
Enzyme-Linked Immunosorbent Assay
Mutation
Heterozygote
Inbred C57BL Mouse
Interleukin-4
Thymidine
Transgenic Mice
Ligation
Immunoglobulins

Keywords

  • a proliferation-inducing ligand (APRIL)
  • common variable immunodeficiency
  • haploinsufficiency
  • murine model
  • Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency. / Lee, John J.; Jabara, Haifa H.; Garibyan, Lilit; Rauter, Ingrid; Sannikova, Tatyana; Dillon, Stacey R.; Bram, Richard J; Geha, Raif S.

In: Journal of Allergy and Clinical Immunology, Vol. 126, No. 6, 12.2010.

Research output: Contribution to journalArticle

Lee, John J. ; Jabara, Haifa H. ; Garibyan, Lilit ; Rauter, Ingrid ; Sannikova, Tatyana ; Dillon, Stacey R. ; Bram, Richard J ; Geha, Raif S. / The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency. In: Journal of Allergy and Clinical Immunology. 2010 ; Vol. 126, No. 6.
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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.",
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T1 - The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency

AU - Lee, John J.

AU - Jabara, Haifa H.

AU - Garibyan, Lilit

AU - Rauter, Ingrid

AU - Sannikova, Tatyana

AU - Dillon, Stacey R.

AU - Bram, Richard J

AU - Geha, Raif S.

PY - 2010/12

Y1 - 2010/12

N2 - 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.

AB - 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.

KW - a proliferation-inducing ligand (APRIL)

KW - common variable immunodeficiency

KW - haploinsufficiency

KW - murine model

KW - Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)

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