title: Soluble CD23 controls IgE synthesis and homeostasis in human B cells.
abstract: CD23, the low-affinity receptor for IgE, exists in membrane and soluble forms. Soluble CD23 (sCD23) fragments are released from membrane (m)CD23 by the endogenous metalloprotease a disintegrin and metalloprotease 10. When purified tonsil B cells are incubated with IL-4 and anti-CD40 to induce class switching to IgE in vitro, mCD23 is upregulated, and sCD23 accumulates in the medium prior to IgE synthesis. We have uncoupled the effects of mCD23 cleavage and accumulation of sCD23 on IgE synthesis in this system. We show that small interfering RNA inhibition of CD23 synthesis or inhibition of mCD23 cleavage by an a disintegrin and metalloprotease 10 inhibitor, GI254023X, suppresses IL-4 and anti-CD40-stimulated IgE synthesis. Addition of a recombinant trimeric sCD23 enhances IgE synthesis in this system. This occurs even when endogenous mCD23 is protected from cleavage by GI254023X, indicating that IgE synthesis is positively controlled by sCD23. We show that recombinant trimeric sCD23 binds to cells coexpressing mIgE and mCD21 and caps these proteins on the B cell membrane. Upregulation of IgE by sCD23 occurs after class-switch recombination, and its effects are isotype-specific. These results suggest that mIgE and mCD21 cooperate in the sCD23-mediated positive regulation of IgE synthesis on cells committed to IgE synthesis. Feedback regulation may occur when the concentration of secreted IgE becomes great enough to allow binding to mCD23, thus preventing further release of sCD23. We interpret these results with the aid of a model for the upregulation of IgE by sCD23.
authors.affiliation: Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Cooper
authors.forename: Philip S
authors.initials: PS
authors.lastname: Hobson
authors.forename: Mark R
authors.initials: MR
authors.lastname: Jutton
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kao
authors.forename: Binia
authors.initials: B
authors.lastname: Drung
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: David J
authors.initials: DJ
authors.lastname: Fear
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Beavil
authors.forename: James M
authors.initials: JM
authors.lastname: McDonnell
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sutton
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gould
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000276:immunology*; D005803:Genes, Immunoglobulin; D006706:Homeostasis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007152:Immunologic Capping; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017464:Receptors, Complement 3d / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D015854:Up-Regulation
chemical_list: C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D004151:Dipeptides; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D017464:Receptors, Complement 3d; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D007073:Immunoglobulin E; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human