Fc receptors in immune thrombocytopenias: a target for immunomodulation?
Bethan Psaila, James B. Bussel
Bethan Psaila, James B. Bussel
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2677-2681. https://doi.org/10.1172/JCI36451.
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Commentary

Fc receptors in immune thrombocytopenias: a target for immunomodulation?

Abstract

In autoimmune disease, Fc receptors (FcRs) form the interface between immune effector cells and their antibody-coated targets, and as such are attractive targets for immunomodulatory therapy. In this issue of the JCI, two highly novel studies of Fc–FcR interactions provide new insights into the role of FcRs in immune thrombocytopenia. Asahi et al. utilized a comprehensive platform of immunological assays to examine the mechanism underlying Helicobacter pylori–associated immune thrombocytopenic purpura, and Ghevaert et al. describe a specially designed antibody that saturates binding sites on fetal platelets without initiating FcγR-mediated platelet phagocytosis, preventing the binding of pathological maternal anti-HLA antibodies that cause fetomaternal alloimmune thrombocytopenia (see the related articles beginning on pages 2939 and 2929, respectively). These reports illustrate how a remarkably detailed molecular understanding of the FcR network may translate into new therapeutic strategies with high clinical impact.

Authors

Bethan Psaila, James B. Bussel

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Figure 1

The activating and inhibitory human FcγRs.

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The activating and inhibitory human FcγRs. Humans have one inhibitory Fc...
Humans have one inhibitory FcγR, FcγRIIB, which contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) as its intracellular signaling domain. Upon binding to Fc fragments, the ITIM recruits negative regulatory signaling proteins. Fc binding to the other FcγRs, including FcγRIIA, induces recruitment of proteins that are involved in activation signaling, via immunoreceptor tyrosine-based activation motifs (ITAMs), which typically consist of a ligand-binding α-chain. FcγRI and FcγRIIIA have signal-transducing γ-chain dimers (indicated by SS). As reported by Asahi et al. in this issue of the JCI (5), the balance between the numbers of inhibitory (FcγRIIB) versus activating (FcγRIIA) FcγRs is disturbed in patients with ITP and H. pylori infection, with downregulation of the inhibitory receptor FcγRIIB. Eradication of H. pylori was found to normalize the FcγR balance and reduce opsonophagocytosis of platelets by macrophages of the reticuloendothelial system. There is one high-affinity receptor, FcγRI. The other FcγRs have low to medium affinity for the Fc portion. Unlike the other transmembrane receptors, FcγRIII is a glycosylphosphatidylinositol-linked protein.