We distinguish FcR for IgG (FcRI/CD64, FcRII/CD32, and FcRIII/CD16), IgE (Fc?RI), IgA (FcRI/CD89), IgM (FcR), and IgA/IgM (Fc/R)

We distinguish FcR for IgG (FcRI/CD64, FcRII/CD32, and FcRIII/CD16), IgE (Fc?RI), IgA (FcRI/CD89), IgM (FcR), and IgA/IgM (Fc/R). 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 definitely associated with allelic variants, changes in ligand binding ability responsible for sponsor defense perturbation. During auto-immune diseases such as rheumatoid arthritis, lupus or immune thrombocytopenia, the autoantibodies and immune complexes lead to swelling through FcR aggregation. We will discuss the part 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 features as a restorative approach for autoimmune diseases. Keywords: immunoglobilins, Fc receptor, antibody treatment, signaling/signaling pathways, inflammatory diseases Fc receptor modes of action Immunoglobulin Fc receptors (FcRs) are membrane molecules expressed by several hematopoietic cells that recognize the Fc region of several immunoglobulin (Ig) classes and subclasses. We distinguish FcR for IgG (FcRI/CD64, FcRII/CD32, and FcRIII/CD16), IgE (Fc?RI), IgA (FcRI/CD89), IgM (FcR), and IgA/IgM (Fc/R). Several other receptors indicated on different cell types also bind Ig molecules: neonatal FcR for IgG (FcRn) on intestinal epithelium, placenta, and endothelium, low affinity Fc?R (Fc?RII/CD23) on B cells and macrophages, and polymeric Ig receptor (pIgR) on mucosal epithelium (1C3). The function BRD9757 of antibodies depends on one hand on their ability to identify antigenic epitopes and, on the other hand, on their dynamic flexibility and their capacity to interact with their cognate FcRs. Engagement of FcRs indicated by leukocytes initiates a number of pro-inflammatory, anti-inflammatory, and immune modulatory functions in the sponsor adaptive immune reactions leading to safety but sometimes also to disease. Several FcRs require the Immunoreceptor Tyrosine-based Activation Motif (ITAM; with the sequence Yxx[L/I]x(6?8)Yxx[L/I]) present in the cytoplasmic tail of the receptor or of associated subunits (FcR or FcRI chain) to induce cell signaling. ITAM-mediated functions include phagocytosis, degranulation, antibody-dependent cellular cytotoxicity (ADCC), cytokine, lipid mediator and superoxide production, all of which depend within the cell type and on outside-in signals induced from the ligand. Engagement of the type I FcRs by immune complexes, induces receptor aggregation followed by activation and recruitment of Src family kinases (SFKs), such as Lyn and Fyn (4). The former induces the phosphorylation of the conserved tyrosines in the ITAM motif, followed by activation and recruitment of the tyrosine kinase Syk. This process activates various proteins involved in cell response, such as Phospholipase C gamma 1 (PLC), Bruton’s tyrosine kinase (Btk), guanine nucleotide exchange element Vav and phosphoinositide 3-kinase (PI3K). Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5) P2) by PLC produces inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) leading to calcium mobilization and protein kinase C (PKC) activation, respectively. Calcium influx and PKC activation promote cell reactions such as degranulation and cytokine production. Vav takes on also an important part in actin cytoskeleton redesigning to control phagocytosis and superoxide production by NADPH oxidase. PI3K catalyzes the phosphorylation of PtdIns(4,5)P2 into PtdIns(3,4,5)P3 in the plasma membrane. Pleckstrin homology domains contained in proteins such as PLC, GRB2-associated-binding protein 2 (Gab2), protein kinase B (PKB/Akt) and Btk, bind PtdIns(3,4,5)P3 therefore recruiting them in the inner leaflet of the plasma membrane advertising their phosphorylation and activation (Number 1, remaining). Open in a separate window Number 1 FcR signaling (e.g., FcRII). (Remaining), the aggregation by an immune complex of FcR bearing ITAM motif (e.g. FcRIIA) 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 PLC and PI3K signaling pathways. The PLC converts PI(4,5)P2 into IP3 and DAG. IP3, Hpt a soluble inositol phosphate, prospects 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) website (Middle), co-ligation between an activating heterologous receptor (e.g., the BCR) and the inhibitory FcR (i.e., BRD9757 FcRIIB) induces phosphorylation of the tyrosine present within the ITIM motif by Lyn (5), leading to the phosphorylation and recruitment of phosphatases (SHIP BRD9757 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 focusing on of FcR bearing ITAM motif (e.g., FcRIIA) induces the phosphorylation of the last tyrosine residue of.