Intravenous Immunoglobulin Treatment in Humans Suppresses Dendritic Cell Function via Stimulation of IL-4 and IL-13 Production

Angela Tjon, Rogier Gent, Haziz Jaadar, P.M. van Hagen, Shanta Mancham, Luc van der Laan, Peter te Boekhorst, Herold Metselaar, Jaap Kwekkeboom

Research output: Contribution to journalArticleAcademicpeer-review

46 Citations (Scopus)


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 Fc gamma RIIb, as well as by modulating IFN-gamma 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 Fc gamma RIIb expression was found, but instead a decreased expression of the activating FcdownregulationRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-gamma R2 subunit of the IFN-gamma R on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of Fc gamma Rs and IFN-gamma R2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-gamma. 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 Fc gamma RIIa and IFN-gamma R2 and not by upregulation of Fc gamma RIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.
Original languageUndefined/Unknown
Pages (from-to)5625-5634
Number of pages10
JournalJournal of Immunology
Issue number12
Publication statusPublished - 2014

Cite this