title: The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function.
abstract: TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NF kappaB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI(-/-) background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.
authors: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: John J
authors: JJ
authors: Lee
authors: Ingrid
authors: I
authors: Rauter
authors: Lilit
authors: L
authors: Garibyan
authors: Esra
authors: E
authors: Ozcan
authors: Tatyana
authors: T
authors: Sannikova
authors: Stacey R
authors: SR
authors: Dillon
authors: Anthony C
authors: AC
authors: Cruz
authors: Richard M
authors: RM
authors: Siegel
authors: Richard
authors: R
authors: Bram
authors: Haifa
authors: H
authors: Jabara
authors: Raif S
authors: RS
authors: Geha
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005362:Ficoll / Q000031:analogs & derivatives / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014301:Trinitrobenzenes / Q000494:pharmacology
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D016328:NF-kappa B; C108467:TNFRSF13B protein, human; C020529:TNP-ficoll; C486361:Tnfrsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D014301:Trinitrobenzenes; D005362:Ficoll