The high-affinity human IgG receptor Fc RI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy
ABSTRACT IgG receptors (FcγRs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis and cancer immunotherapy. A few FcγRs have the ability to bind monomeric IgG, i.e. high-affinity mouse mFcγRI, mFcγRIV and human hFcγRI, whereas all others bind IgG only when aggregated, in complexes or bound to cells or surfaces, i.e. low-affinity mouse mFcγRIIB, mFcγRIII and human hFcγRIIA/B/C and hFcγRIIIA/B. Although it was proposed that high-affinity FcγRs are occupied by circulating IgG, multiple roles for mFcγRI and mFcγRIV have been reported in vivo. The potential roles of hFcγRI that is expressed on monocytes, macrophages and neutrophils, have however not been reported. We therefore investigated the role of hFcγRI in antibody-mediated models of disease and therapy by generating hFcγRI-transgenic mice deficient for multiple endogenous FcRs. hFcγRI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, active and passive systemic anaphylaxis. We identified monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction. Finally, hFcγRI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Altogether, our results unravel novel capabilities of human FcγRI that confirm the role of high-affinity IgG receptors in vivo.
Full-textDOI: · Available from: Nico Van Rooijen, Aug 27, 2015
- SourceAvailable from: Christine A Petersen
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- "al. (2010) previously characterized how antibody concentration during opsonization can influence the macrophage response, with higher concentrations of antibodies promoting an immunoregulatory response that produces increasing levels of IL-10 . Less is known of the immunomodulatory properties of ICs, although their involvement in inflammation is clear from their ability to promote the Arthus reaction and autoimmunity , . A role for ICs in promoting a pro-inflammatory response during infection with intracellular pathogens is relatively unexplored. "
ABSTRACT: Footpad infection of C3HeB/FeJ mice with Leishmania amazonensis leads to chronic lesions accompanied by large parasite loads. Co-infecting these animals with L. major leads to induction of an effective Th1 immune response that can resolve these lesions. This cross-protection can be recapitulated in vitro by using immune cells from L. major-infected animals to effectively activate L. amazonensis-infected macrophages to kill the parasite. We have shown previously that the B cell population and their IgG2a antibodies are required for effective cross-protection. Here we demonstrate that, in contrast to L. major, killing L. amazonensis parasites is dependent upon FcRγ common-chain and NADPH oxidase-generated superoxide from infected macrophages. Superoxide production coincided with killing of L. amazonensis at five days post-activation, suggesting that opsonization of the parasites was not a likely mechanism of the antibody response. Therefore we tested the hypothesis that non-specific immune complexes could provide a mechanism of FcRγ common-chain/NADPH oxidase dependent parasite killing. Macrophage activation in response to soluble IgG2a immune complexes, IFN-γ and parasite antigen was effective in significantly reducing the percentage of macrophages infected with L. amazonensis. These results define a host protection mechanism effective during Leishmania infection and demonstrate for the first time a novel means by which IgG antibodies can enhance killing of an intracellular pathogen.PLoS ONE 09/2014; 9(9):e106426. DOI:10.1371/journal.pone.0106426 · 3.23 Impact Factor
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- "Furthermore, hFcγRI and hFcγRIIA were identified as each individually sufficient to mediate ASA in transgenic mice, resulting in both hypothermia and death (9, 136). hFcγRI-dependent ASA required neutrophils and the release of platelet activating factor (9). These data demonstrate that hFcγR expressed on neutrophils and monocytes can mediate fatal anaphylactic reactions in vivo. "
ABSTRACT: The biological activities of human IgG antibodies predominantly rely on a family of receptors for the Fc portion of IgG, FcγRs: FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB, FcRL5, FcRn, and TRIM21. All FcγRs bind IgG at the cell surface, except FcRn and TRIM21 that bind IgG once internalized. The affinity of FcγRs for IgG is determined by polymorphisms of human FcγRs and ranges from 2 × 10(4) to 8 × 10(7) M(-1). The biological functions of FcγRs extend from cellular activation or inhibition, IgG-internalization/endocytosis/phagocytosis to IgG transport and recycling. This review focuses on human FcγRs and intends to present an overview of the current understanding of how these receptors may contribute to various pathologies. It will define FcγRs and their polymorphic variants, their affinity for human IgG subclasses, and review the associations found between FcγR polymorphisms and human pathologies. It will also describe the human FcγR-transgenic mice that have been used to study the role of these receptors in autoimmune, inflammatory, and allergic disease models.Frontiers in Immunology 05/2014; 5:254. DOI:10.3389/fimmu.2014.00254
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ABSTRACT: Neutrophils are notorious for their efficacy in microbial killing. Various mechanisms, such as phagocytosis, production of ROS, cytokines/chemokines and lipid mediators, degranulation of antimicrobials and enzymes, as well as NETosis contribute to this capacity. However, every incidence of neutrophil activation bears a risk to cause damage to the host. Several distinct steps, i.e., adhesion to endothelial cells, transmigration, chemotaxis, cytokine stimulation, and TLR signaling, are thought to control the extent of neutrophil activation. In the absence of a microbial stimulus, other pathways can induce neutrophil activation, among which FcR-induced activation when neutrophils encounter ICs. In these situations (inflammation, autoimmunity, allergy), neutrophils may act as primary or secondary effectors of immune reactions. In the presence of circulating ICs, neutrophils can indeed get stimulated directly in the bloodstream and trigger an immune response. Upon deposition of antibody complexes inside of tissues, neutrophils are first recruited and primed before being highly activated to amplify the ongoing inflammation. This review focuses on the engagement, activation, and responses of neutrophils to antibody ICs, inside of tissues or in the vasculature.Journal of leukocyte biology 03/2013; 94(4). DOI:10.1189/jlb.1212623 · 4.99 Impact Factor