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

• Published in: Journal of allergy and clinical immunology 2010-12, Vol.126 (6), p.1234-1241.e2
• Main Authors: Lee, John J., MD, Jabara, Haifa H., BS, Garibyan, Lilit, MD, PhD, Rauter, Ingrid, PhD, Sannikova, Tatyana, BS, Dillon, Stacey R., PhD, Bram, Richard, MD, PhD, Geha, Raif S., MD
• Format: Article
• Language: English
• Subjects: a proliferation-inducing ligand (APRIL); Allergy and Immunology; Animals; Antibody Formation - genetics; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biological and medical sciences; Calcium; Cell Proliferation; Cells, Cultured; Cloning; common variable immunodeficiency; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Ficoll - analogs & derivatives; Ficoll - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; haploinsufficiency; Haploinsufficiency - immunology; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulins; Immunopathology; Ligands; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; murine model; Mutant Proteins - genetics; Mutant Proteins - immunology; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Software; Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI); Transmembrane Activator and CAML Interactor Protein - genetics; Transmembrane Activator and CAML Interactor Protein - immunology; Transmembrane Activator and CAML Interactor Protein - metabolism; Trinitrobenzenes - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2010.08.017

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.