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

• DOI: 10.4049/jimmunol.1301260
• Publication Date: 2014-05-08T01:38:43Z
• Authors: Angela S W Tjon; Rogier van Gent; Haziz Jaadar; P Martin van Hagen; Shanta Mancham; Luc J W van der Laan; Peter A W te Boek...; Herold J Metselaar; Jaap Kwekkeboom
• Keywords: Adult; Male; EMC MM-02-72-02; EMC MM-04-20-02-A; EMC MM-04-20-01; EMC MM-04-47-07; Autoimmune Diseases; Mice; 03 medical and health sciences; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Animals; Humans; Immunologic Factors; Aged; Receptors, Interferon; Inflammation; Interleukin-13; Dose-Response Relationship, Drug; Interleukins; Immunoglobulins, Intravenous; Dendritic Cells; Middle Aged; Interleukin-33; 3. Good health; Gene Expression Regulation; EMC MM-02-41-04; Female; Interleukin-4

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.