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...
