Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools

Abstract

Fc receptors (FcRs) belong to the ITAM-associated receptor family. FcRs control the humoral and innate immunity which are essential for appropriate responses to infections and prevention of chronic inflammation or auto-immune diseases. Following their crosslinking by immune complexes, FcRs play various roles such as modulation of the immune response by released cytokines or of phagocytosis. Here, we review FcR involvement in pathologies leading notably to altered intracellular signaling with functionally relevant consequences to the host, and targeting of Fc receptors as therapeutic approaches. Special emphasis will be given to some FcRs, such as the FcαRI, the FcγRIIA and the FcγRIIIA, which behave like the ancient god Janus depending on the ITAM motif to inhibit or activate immune responses depending on their targeting by monomeric/dimeric immunoglobulins or by immune complexes. This ITAM duality has been recently defined as inhibitory or activating ITAM (ITAMi or ITAMa) which are controlled by Src family kinases. Involvement of various ITAM-bearing FcRs observed during infectious or autoimmune diseases is associated with allelic variants, changes in ligand binding ability responsible for host defense perturbation. During auto-immune diseases such as rheumatoid arthritis, lupus or immune thrombocytopenia, the autoantibodies and immune complexes lead to inflammation through FcR aggregation. We will discuss the role of FcRs in autoimmune diseases, and focus on novel approaches to target FcRs for resolution of antibody-mediated autoimmunity. We will finally also discuss the down-regulation of FcR functionality as a therapeutic approach for autoimmune diseases.

Keywords: Fc receptor; antibody treatment; immunoglobilins; inflammatory diseases; signaling/signaling pathways.

Figure 1

FcR signaling (e.g., FcγRII). (Left), the aggregation by an immune complex of FcR bearing ITAM motif (e.g. FcγRIIA) induces phosphorylation of the two ITAM tyrosine residues by Src kinases Lyn and Fyn responsible for recruitment and phosphorylation of Syk inducing cellular activation through PLCγ and PI3K signaling pathways. The PLCγ converts PI(4,5)P₂ into IP₃ and DAG. IP₃, a soluble inositol phosphate, leads to Ca²⁺ mobilization while DAG activate MAPK.PI3K converts PI(4,5)P₂ to PI(3,4,5)P₃ allowing recruitment of signal intermediates through their pleckstrin homology (PH) domain (Middle), co-ligation between an activating heterologous receptor (e.g., the BCR) and the inhibitory FcR (i.e., FcγRIIB) induces phosphorylation of the tyrosine present within the ITIM motif by Lyn (5), leading to the phosphorylation and recruitment of phosphatases (SHIP or SHP). The phosphatases PTEN and SHIP1/2 regulate cellular levels of PI(3,4,5)P₃ by hydrolyzing it to PI(4,5)P₂ and PI(3,4)P₂, respectively. These dephosphorylations inhibit cell proliferation. (Right), monovalent targeting of FcR bearing ITAM motif (e.g., FcγRIIA) induces the phosphorylation of the last tyrosine residue of the ITAM motif by Lyn responsible for transient recruitment of Syk followed by that of SHP-1 which abrogates the activation signal.

Figure 2

Organization and conformational rearrangements of the IgE Fc. (left), IgE and the binding sites to FcεRI (green) and to CD23 (pink) [adapted from Pennington et al. (24)] (Middle and Right). Representation of the open and closed conformations, respectively, of the IgE Fc Cε3–4 domains, and the mutual allosteric inhibition by FcεRIα (green) and CD23 (pink).

Figure 3

Human type I and II Fc receptors. Schematic representation of human Fc receptors at the cell membrane and their association or not with the FcRγ-chain dimer and the FcεRIβ chain, red circles represent the tyrosine residues. The FcγRIIIB is anchored into the outer leaflet of the plasma membrane by a phosphatidylinositol-glycan (green circle).