IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses

Abstract

Intravenous immunoglobulin (IVIg) has been used in the treatment of several autoimmune and inflammatory diseases. However, its mechanism of action remains incompletely understood. Here, we investigated the possibility that IVIg induces its anti-inflammatory effects through activating Fc␥ receptors bearing an immunoreceptor tyrosine-based activation motif (ITAM) in the FcR␥ signaling adaptor. Recently, the concept of inhibitory ITAM (ITAMi) has emerged as a new means to negatively control the immune response. We found that interaction of IntroductionIntravenous immunoglobulin (IVIg) is used not only for treatment of immune deficiencies, but also constitutes a therapeutic option in a large number of autoimmune, allergic, and inflammatory diseases. 1,2 Different mechanisms have been suggested as responsible for the anti-inflammatory activity of IVIg such as, its content of natural polyreactive Abs reactive, its ability to stimulate or block cellular receptors for immunoglobulins (Igs; Fc receptors, or FcRs), inhibition of the complement cascade, modulation of cytokine production, neutralization of auto-antibodies, and differential antibody glycosylation. 1,[3][4][5][6] Fc␥R exist in multiple isoforms comprising high-affinity and low-affinity receptors. In humans, there is one high-affinity IgG receptor, Fc␥RI (CD64), and 2 families of low-affinity IgG receptors, Fc␥RIIA, IIB, and IIC (CD32), and Fc␥RIIIA and IIIB (CD16). Fc␥RI and Fc␥RIIIA are associated with the common signaling adaptor FcR␥, whereas Fc␥RIIA, Fc␥RIIB and Fc␥RIIC are single-chain receptors and Fc␥RIIIB is a glycosyl-phosphatidyl inositol (GPI)-anchored receptor. In mice, there is no homolog to Fc␥RIIA and Fc␥RIIIB, but they express another FcR␥-associated receptor, the Fc␥RIV, that is not found in humans. 7 The FcR␥ chain contains a tyrosine-based activation motif (ITAM) and is the prime effector of the proinflammatory activity of IgG in inflammatory and autoimmune diseases. Cross-linking of activating Fc␥Rs, such as Fc␥RI, Fc␥RIII and Fc␥RIV, by immune complexes, launches transmembrane signaling after phosphorylation of ITAM tyrosine residues in the receptor-associated FcR␥ subunit by kinases of the Src family. 8,9 For example, Fc␥RIII multimerization exacerbates inflammation in several models of immune complex-mediated diseases. [10][11][12] By contrast, Fc␥RIIB, which is conserved in mice and humans, is a single-chain inhibitory Fc␥R. Fc␥RIIB contains tyrosine-based inhibition motif (ITIM) in its cytoplasmic region. 13 Inhibition was shown to depend on the isotype of IgG and on Fc␥RIIB expression levels. Up-regulation of the latter was proposed as one of the mechanisms for the anti-inflammatory action of IVIg therapy. 1 Fc␥R anti-inflammatory activities of IVIg are mediated through both Fc␥RIIB-and/or Fc␥RIIIA-dependent and Fc␥R-independent mechanisms. 14-16 However, mechanisms of action of IVIg through activating Fc␥RIII are not yet fully elucidated.The classic concept of the functional polarity of ITIM and ITAM motifs has been recently reeval...

Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells

“…on May 11, 2018. by guest www.bloodjournal.org From reflects antigen uptake/endocytic ability, 36 a defining property of immature DCs. However, an increased ability to capture antigens via receptor-mediated endocytosis has also been demonstrated in mature DCs 37 and has been proposed to confer mature DCs with the ability to capture and present specific antigens and pathogens previously recognized by the immune system.…”

Properties of mouse and human IgG receptors and their contribution to disease models

“…The FcR␥-chain is, indeed, also required for the expression of macrophage-inducible C-type lectin (Mincle) 44 and osteoclast-associated receptor (OSCAR), 45 and contributes to the signal transduction of several other molecules. Fc␥RIIB Ϫ/Ϫ mice were reported in 1996, 46 Fc␥RIII Ϫ/Ϫ mice in 1996 47 and 1999, 48 [61][62][63][64] have also been reported to be involved/mandatory. Indeed, an increasing number of reports have revealed that activating Fc␥RIII mediates the anti-inflammatory effects of intravenous immunoglobulin in experimental thrombocytopenia when expressed on DCs 61 or on macrophages, 62 in allergic airway inflammation when expressed on NKT cells, 63 and in a nonimmune inflammation model of obstructive nephropathy.…”

“…Indeed, an increasing number of reports have revealed that activating Fc␥RIII mediates the anti-inflammatory effects of intravenous immunoglobulin in experimental thrombocytopenia when expressed on DCs 61 or on macrophages, 62 in allergic airway inflammation when expressed on NKT cells, 63 and in a nonimmune inflammation model of obstructive nephropathy. 64 Using knockout mice for a particular FcR was for a long time considered the standard approach to address the function of a particular Fc␥R in vivo (ie, by studying the effect of its absence). Recently, however, the generation of multiple FcR-knockout mice has enabled the study of a particular FcR in the absence of most/all other FcRs.…”

Effect of trastuzumab interchain disulfide bond cleavage on Fcγ receptor binding and antibody-dependent tumour cell phagocytosis

“…However, it is unknown how the inhibitory FcgRIIB is involved in our ADCP system as compared with FcgRIA and FcgRIIA. In addition, FcgRIII was reported not only to exert phagocytosis but also to induce inhibitory signalling (28). In our previous study, interchain S S bond cleavage of rituximab resulted in increased binding affinity for FcgRIIIA and decreased ADCC (19), suggesting inhibitory signalling through FcgRIIIA.…”