title: Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production.
abstract: High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33-Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: Angela S W
authors.initials: AS
authors.lastname: Tjon
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: Rogier
authors.initials: R
authors.lastname: van Gent
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: Haziz
authors.initials: H
authors.lastname: Jaadar
authors.affiliation: Department of Internal Medicine and Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: P
authors.initials: P
authors.lastname: Martin van Hagen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.affiliation: Department of Surgery, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands; and.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands.
authors.forename: Peter A W
authors.initials: PA
authors.lastname: te Boekhorst
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands; j.kwekkeboom@erasmusmc.nl.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D007155:Immunologic Factors / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology*; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D017471:Receptors, Interferon / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D018793:Interleukin-13; D000067596:Interleukin-33; D015847:Interleukin-4; D007378:Interleukins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C506536:IL33 protein, human; C508598:IL4 protein, human