Fc-Gamma-RIIB Signaling in B-Cells
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Fc-Gamma-RIIB Signaling in B-Cells

The ability of the immune system to respond appropriately to foreign antigen is dependent on a delicate balance of activating and inhibitory signals. Although positive signaling is essential for the generation of effective immunity, counterbalancing the immune response by inhibitory pathways is equally important. Loss of inhibitory signaling is often associated with autoreactivity and unchecked inflammatory responses, illustrating the essential role these systems play in immune regulation (Ref.1). Pairing of activation and inhibition is therefore, necessary to modulate immune responses. The activation threshold of various cells in the immune system is tuned by immune inhibitory receptors. The inhibitory Fc (Crystalline Fragment) Receptor, Fc-Gamma-RIIB (Fc-Gamma Receptor-IIB), is one of the critical molecules for the regulation of immune responses through antibodies (Ref.2). Fc-Gamma-RIIB belongs to the class of Fc-Gamma-Rs, which recognize the Fc portion of the IgG (Immunoglobulin-G). Two general, recognized classes of Fc-Gamma-Rs are: the activation receptors (Fc-GammaRI, Fc-Gamma-RIIA and Fc-Gamma-RIIIA), characterized by the presence of a cytoplasmic ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) associated with the receptor; and the inhibitory receptor (Fc-Gamma-RIIB), characterized by the presence of an ITIM (Immunoreceptor Tyrosine-Based Inhibitory Motif) sequence. The inhibitory IgG Fc Receptor Fc-Gamma-RIIB is broadly expressed on hematopoietic cells, but its function was initially characterized in B-Cells, where it regulates antibody production, cytokine release, proliferation, and cell survival (Ref.3).

B-Cells constitute an important part of the immune system, dedicated to making of Igs or antibodies. B-Cell activation and other effector functions following an antigenic stimulation are brought about by the ITAMs contained in the BCR (B-Cell Receptor). Antigenic stimulation of BCR is a central event in the immune response. In contrast, antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor Fc-Gamma-RIIB (Ref.4). Fc-Gamma-RIIB is the only IgG receptor expressed on B-Cells. It encodes a single chain glycoprotein characterized by a ligand-binding extracellular domain highly homologous to its activation counterparts, but containing the distinctive inhibitory ITIM sequence in its cytoplasmic domain. Expression of the inhibitory Fc-Gamma-RIIB on B-Cells provides a mechanism for the suppressive effects of immune complexes on antibody production, particularly during the germinal center reaction. The inhibitory ITIM motif, embedded in the cytoplasmic domain of the single-chain Fc-Gamma-RIIB molecule is defined as a 13-amino acid sequence (Ala-Glu-Asn-Thr-Ile-Thr-Tyr-Ser-Leu-Leu-Lys-His-Pro) both necessary and sufficient to mediate the inhibition of BCR-generated Ca2+ (Calcium) mobilization and cellular proliferation (Ref.1). The biological significance of Fc-Gamma-RIIB-dependent B-Cell inhibition caused by IgG containing immune complexes is to control antibody synthesis (Ref.5).

Interaction of antigen with surface Igs on B-Cells is communicated to the interior of the B-Cell by the disulfide-linked heterodimer of Ig-Alpha (CD79A Antigen) and Ig-Beta (CD79B Antigen) proteins, which are associated with IgM in the B-Cell membrane to form the functional BCR. Signaling through BCR is critical for differentiation, proliferation, maturation and effector functions of B lymphocytes. The cytoplasmic tail of Ig-Alpha and Ig-Beta heterodimer contains ITAMs with which the tyrosine kinases associate. The ITAMs become phosphorylated on tyrosine residues, and the active tyrosine kinases and the phosphorylated receptor tails then initiate intracellular signaling pathways. Src Kinases such as Lyn regulate a multitude of phosphorylation events that also involves the activation of SYK (Spleen Tyrosine Kinase) and Tec (BTK (Brutons Tyrosine Kinase)) families of tyrosine kinases. These kinases coordinately phosphorylate downstream substrates that include adaptors such as BLNK (B-Cell Linker Protein) and effectors such as PLC-Gamma2 (Phopholipase-C-Gamma2). Ultimately, a cascade of signaling pathways, including the Ras, PI3K(Phosphatidylinositde-3 Kinase) and Calcium Signaling leads to transcriptional activation of target genes and contribute to the differentiation and proliferation of antigen-specific B-Cells, an essential component of the early immune response (Ref.6).

In the later phases of the immune response, binding of the circulating immune complex to its cognate B-Cells colligates BCR with Fc-Gamma-RIIB through the Fc portion of the IgG antibody, resulting in negative regulation of BCR-mediated activation signals. The inhibitory activity of Fc-Gamma-RIIB depends on the presence of an ITIM within its cytoplasmic tail, which counteracts the signal transduction triggered by the ITAM-containing BCR. In B-Cells, phosphorylation of the tyrosine of the ITIM motif occurs upon BCR coligation and is required for its inhibitory activity. This modification generates an SH2 recognition domain that is the binding site for the inhibitory signaling molecule SHIP (SH2-Containing Inositol Phosphatase) that leads to the abrogation of ITAM activation signaling by hydrolyzing the membrane inositol phosphate PIP3 (PhosphatidylInositol-3, 4, 5-trisphosphate), itself the product of receptor activation (Ref.7). In B-Cells, Fc-Gamma-RIIB displays three separable inhibitory activities, two of which are dependent on the ITIM motif and one that is independent of this motif. Co-engagement of Fc-Gamma-RIIB to the ITAM-containing BCR leads to tyrosine phosphorylation of the ITIM by the Lyn kinase, recruitment of SHIP, and the inhibition of ITAM-triggered Ca2+ mobilization and cellular proliferation. These two inhibitory activities result from different signaling pathways, with Ca2+ inhibition requiring the phosphatase activity of SHIP to hydrolyze PIP3 and the ensuing dissociation of PH (Pleckstrin-Homology) domain-containing proteins like BTK and PLC-Gamma2 from the membrane. Inhibition of PLC-Gamma2 results in inhibition of the process of conversion of PIP2 (Phosphatidylinositol 4,5-bisphosphate). The net effect is to block Ca2+ influx through the capacitance-coupled CaCn (Ca2+ Channel) and prevent sustained Calcium Signaling, which prevents Calcium-dependent processes such as Degranulation, Phagocytosis, ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity), cytokine release and Proinflammatory Activation (Ref.6). 

Arrest of proliferation in B-Cells is also dependent on the ITIM pathway, through the activation of the adaptor protein DOK1 and subsequent inactivation of MAPKs (Mitogen-Activated Protein Kinases). SHIP can affect proliferation in several ways. Through its catalytic phosphatase domain, SHIP can prevent recruitment of the PH domain survival factor Akt by hydrolysis of PIP3 (Ref.7). Hydrolysiis of PIP3 also blocks the PIP3/PDK-1 (Phosphoinositide-Dependent Kinase-1)/Akt pathway, thus affecting B-cell survival. SHIP also contains PTB domains that could act to recruit DOK1 to the membrane and provide access to the Lyn kinase that is involved in its activation (Ref.1). DOK1 is involved in the negative regulation of the MAPK pathway activated by antigen-stimulation of BCR through SYK, SHC , GRB2 (Growth Factor Receptor-Bound Protein-2), SOS, and Ras (Ref.4). The third inhibitory activity displayed by Fc-Gamma-RIIB is independent of the ITIM sequence and is displayed upon homoaggregation of the receptor in germinal center B-Cells. Under these conditions of Fc-Gamma-RIIB clustering, a proapoptotic signal is generated through the transmembrane sequence in a BTK-dependent manner by JNK (c-Jun Kinase) activation. With co-engagement of Fc-Gamma-RIIB and BCR, however, SHIP recruitment to the receptors ITIM may prevent the BTK-dependent proapoptotic signal, thus favoring B-Cell survival (Ref.3). This activity has only been reported in B-Cells and has been proposed to act as a means of maintaining peripheral tolerance for B-Cells that have undergone somatic hypermutation. In addition to its expression on B cells, Fc-Gamma-RIIB is widely expressed on effector cells such as macrophages, neutrophils, and mast cells, missing only from T-Cells and NK (Natural Killer) cells (Ref.1).

The strength and nature of immune responses are determined by the pairing of activating and inhibitory receptors. Thus, in vivo, abnormalities in ITAM-bearing receptors can result in selective immunodeficiencies and, conversely, dysfunctional ITIM-bearing receptors can lead to potentially fatal autoimmune disorders. Over the past several years, transmembrane receptors containing ITIMs have been identified on virtually all cells in the immune system and also on some non-hematopoietic cells. Most of these ITIM-containing transmembrane receptors have homologous activating receptors that associate with ITAM-containing subunits (Ref.3). It is postulated that the beneficial effects of intravenous gamma globulin in the treatment of immune disorders may be attributable, at least in part, to engagement of Fc-Gamma-RIIB (Ref.8). Elucidation of the mechanisms by which Fc-Gamma-RIIB inhibits immune responses, may lead to the development of therapeutic strategies for the treatment of autoimmune and inflammatory pathologies that specifically target Fc-Gamma-RIIB or its effectors (Ref.2).