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.

Ability of Interleukin‐33– and Immune Complex–Triggered Activation of Human Mast Cells to Down‐Regulate Monocyte‐Mediated Immune Responses

“…In vivo, IL-33 has been implicated in the ability of mast cells to contribute to the development of arthritis in murine experimental models (23,24), and high levels of IL-33 have been found in the serum and synovial fluid of patients with RA and those with other inflammatory arthritides (25). In addition to these proinflammatory properties, which are consistent with the described role of IL-33 as an alarmin, recent evidence suggests that this cytokine can also mediate immunoregulatory responses in various settings, by, for example, promoting regulatory T and B cell activity and suppressing monocyte activation through its effects on basophils (26)(27)(28)(29)(30)(31). Thus, similar to the findings regarding mast cells, the specific functions of IL-33 in the pathogenesis of autoimmune diseases, including arthritis, are still unclear (32,33).…”

Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies

“…CVID, a rare disease characterized by antibody deficiency, infectious and inflammatory conditions [26,27] is characterized by multiple abnormalities in the immune system beyond humoral immunity involving dendritic cells (DCs), CD8 T cells, CD4 T cells, invariant natural killer T (iNKT) cells, and regulatory T cells (Tregs) [28][29][30]. In our study, we analyzed the in vivo frequency and effector functions of monocyte subsets in CVID patients.…”

IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

“…A very recent publication offers an intriguing in vivo model to reproduce these findings in humans [30]. Studying patients with primary immune deficiency, it was found that IVIG therapy suppresses dendritic cell function via IL-33-mediated induction of IL-4 and IL-13.…”