title: Aberrant antibody affinity selection in SHIP-deficient B cells.
abstract: The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5'-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Wai-Hang
authors.initials: WH
authors.lastname: Leung
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tarasenko
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Biesova
authors.forename: Hemanta
authors.initials: H
authors.lastname: Kole
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Walsh
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007372:Interferons / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology*; D011946:Receptors, Antigen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000941:Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011946:Receptors, Antigen; D007372:Interferons; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases