Cutting Edge: Intravenous Ig Inhibits Invariant NKT Cell-Mediated Allergic Airway Inflammation through Fc gamma RIIIA-Dependent Mechanisms

Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Hôpital Necker, Paris 75783, France.
The Journal of Immunology (Impact Factor: 4.92). 02/2011; 186(6):3289-93. DOI: 10.4049/jimmunol.1003076
Source: PubMed


Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.

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Available from: Jean-Marc Gombert, Feb 18, 2014
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    • "Siragam et al. confirmed the critical role of activating Fcγ receptors in the anti-inflammatory effects of IVIG in vivo [5]. In an invariant NKT(iNKT) cell-mediated allergic airway inflammation model, IVIG regulates iNKT cells through activating Fcγ receptor, FcγRIIIa [6]. A recent study also confirmed that the inhibitory effect of IVIG on T cells responses is independent of the inhibitory receptor FcγRIIb, supporting the role of activating Fcγ receptors in IVIG therapy [7]. "
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    ABSTRACT: Intravenous immunoglobulin has long been used in treating autoimmune diseases, although mechanisms remain uncertain. Activating Fcγ receptors are receptors of IgG and reported to be essential in intravenous immunoglobulin (IVIG) therapy. Therefore, we hypothesized natural killer (NK) cells, which express abundant activating Fcγ receptors, are the potential cellular target. In experimental autoimmune encephalomyelitis (EAE), we demonstrated that IgG suppressed disease development in intact, but not in NK cell depleted mice. Adoptive transfer of IgG-treated NK cell could protect mice against EAE, and suppressed interferon γ and interleukin 17 production. The percentage of CD4(+)Foxp3(+) regulatory T cells was significantly increased. The increase of regulatory T cells was also observed in IgG-treated EAE mice but not in NK cell depleted mice. In vitro experiments confirmed that IgG-treated NK cells enhanced regulatory T cell induction from naïve CD4(+) T cells. Interestingly, cells from draining lymph nodes produced more interleukin 2 after the adoptive transfer of IgG-treated NK cells. We neutralized interleukin 2 and the induction of CD4(+)Foxp3(+) T cells by IgG-treated NK cells was significantly reduced. To our knowledge, we identified for the first time the critical role of NK cells in the mechanism of IgG-induced induction of Treg cells in treatment of autoimmunity.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "Most recently, a putative mechanism involving production of IL-33 and secretion of Th2 cytokines by basophils has been convincingly shown [15]. It remains unclear to what extent this mechanism contributes to the overall anti-inflammatory effect of IVIG, which is known to employ a number of different mechanisms to achieve anti-inflammatory effects, including inhibitory signalling through FcγRIIB [23], induction of Tregs [24], attenuation of complement activation [25], [26], recently described new effects on iNKT cells [27] and TH17 cells [28] as well as many more (reviewed in [6], [9], [11], [16], [29]–[31]). Importantly, the anti-inflammatory effect of highly sialylated Fc in models beyond K/BxN needs to be confirmed. "
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    ABSTRACT: It has been proposed that the anti-inflammatory effects of intravenous immunoglobulin (IVIG) might be due to the small fraction of Fc-sialylated IgG. In this study we biochemically and functionally characterized sialic acid-enriched IgG obtained by Sambucus nigra agglutinin (SNA) lectin fractionation. Two main IgG fractions isolated by elution with lactose (E1) or acidified lactose (E2) were analyzed for total IgG, F(ab')(2) and Fc-specific sialic acid content, their pattern of specific antibodies and anti-inflammatory potential in a human in vitro inflammation system based on LPS- or PHA-stimulated whole blood. HPLC and LC-MS testing revealed an increase of sialylated IgG in E1 and more substantially in the E2 fraction. Significantly, the increased amount of sialic acid residues was primarily found in the Fab region whereas only a minor increase was observed in the Fc region. This indicates preferential binding of the Fab sialic acid to SNA. ELISA analyses of a representative range of pathogen and auto-antigens indicated a skewed antibody pattern of the sialylated IVIG fractions. Finally, the E2 fraction exerted a more profound anti-inflammatory effect compared to E1 or IVIG, evidenced by reduced CD54 expression on monocytes and reduced secretion of MCP-1 (CCL2); again these effects were Fab- but not Fc-dependent. Our results show that SNA fractionation of IVIG yields a minor fraction (approx. 10%) of highly sialylated IgG, wherein the sialic acid is mainly found in the Fab region. The tested anti-inflammatory activity was associated with Fab not Fc sialylation.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "The resulting reduction in pro-inflammatory cytokine production and increasing anti-inflammatory cytokine production further contributes to the anti-inflammatory and immunomodulatory activity of IVIg [113]. IVIg also inhibited invariant natural killer T-cell activation mediated through FcγRIIIA receptor effects [114]. IgG can determine the CD1 expression profile of monocyte-derived dendritic cells as this is mediated, at least in part, by FCγIIA receptors. "
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    ABSTRACT: ABSTRACT: Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.
    Full-text · Article · Mar 2012 · Critical care (London, England)
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