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Blood, 10 September 2009, Vol. 114, No. 11, pp. 2254-2262. Prepublished online as a Blood First Edition Paper on July 15, 2009; DOI 10.1182/blood-2008-11-189720. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-11-189720v1 114/11/2254    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Lee, J. J. Articles by Geha, R. S. PubMed PubMed Citation Articles by Lee, J. J. Articles by Geha, R. S. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function John J. Lee1, Ingrid Rauter1, Lilit Garibyan1, Esra Ozcan1, Tatyana Sannikova1, Stacey R. Dillon2, Anthony C. Cruz3, Richard M. Siegel3, Richard Bram4, Haifa Jabara1, and Raif S. Geha1 1 Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA; 2 Department of Immunology, ZymoGenetics Inc, Seattle, WA; 3 Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD; and 4 Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 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 NFB 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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