title: Impaired B cell receptor signaling is responsible for reduced TACI expression and function in X-linked immunodeficient mice.
abstract: Immune response to T cell independent type 2 (TI-2) Ags, such as bacterial polysaccharides, is severely impaired in X-linked immunodeficient (XID) mice. In this study, we investigated the involvement of a proliferation-inducing ligand (APRIL) or BAFF and their receptors in the unresponsiveness of XID mouse to TI-2 Ags. We discovered that whereas serum BAFF levels were increased, the expression of the APRIL and BAFF receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) was severely reduced in XID B cells. Moreover, B cells from XID mouse were unable to secrete Igs in response to APRIL or BAFF. In correlation with reduced TACI expression and impaired TACI function, APRIL or BAFF did not activate the classical NF-κB pathway in XID cells. Also correlating with the unaltered expression of BAFF receptor, BAFF stimulation induced the activation of the alternative NF-κB pathway in XID cells. Moreover, activation of MAPK pathway was ablated in APRIL-stimulated XID cells. Prestimulation of XID B cells with the TLR9 agonist, CpG led to a significant increase in TACI expression and restored TACI-mediated functions. CpG prestimulation also restored TACI-mediated signaling in APRIL- or BAFF-stimulated XID B cells. Finally, immunization of XID mouse with the prototype TI-2 Ag NP-Ficoll induced IgG and IgM Abs when CpG was given with NP-Ficoll. Collectively, these results suggest that reduced TACI expression is responsible for the unresponsiveness of XID mouse to TI-2 Ags and BCR activation controls TACI expression.
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, 20892.
authors.forename: Kadriye
authors.initials: K
authors.lastname: Uslu
authors.forename: Adam S
authors.initials: AS
authors.lastname: Coleman
authors.forename: Windy R
authors.initials: WR
authors.lastname: Allman
authors.forename: Nora
authors.initials: N
authors.lastname: Katsenelson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Alugupalli
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akkoyunlu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D053264:B-Cell Activating Factor / Q000097:blood / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C486361:Tnfrsf13b protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse