Fc fragment of immunoglobulin G receptor IIb (FcγRIIb)

Fc fragment of immunoglobulin G receptor IIb (FcγRIIb) is the only inhibitory type I Fc gamma receptor in humans and mice. It is a low affinity receptor for the Fc region of immunoglobulin G (IgG) and plays a crucial role in regulating immune responses by dampening the activation signals from other activating Fc gamma receptors[1]. The receptor exists in two major isoforms, FcγRIIb1 and FcγRIIb2, generated through alternative mRNA splicing. FcγRIIb1 is highly expressed on B cells and contains an additional sequence that tethers it to the cell membrane, while FcγRIIb2 is expressed on basophils and myeloid cells and allows for rapid receptor internalization[1]. Both isoforms contain the critical ITIM signaling motif in their cytoplasmic regions, which is responsible for their inhibitory function. Structurally, FcγRIIb consists of two immunoglobulin-like domains arranged at approximately a 70-degree angle, creating a heart-shaped structure[3]. The extracellular domains share 95% identity with the activating receptor FcγRIIa and are nearly identical to FcγRIIc[1]. The IgG binding site is located in the BC, C'E, and FG loops of the second domain[3]. The primary function of FcγRIIb is to inhibit immune cell activation. When immune complexes bind to FcγRIIb, the ITIM domain becomes phosphorylated, recruiting inositol phosphatases SHIP1 and SHIP2[1]. This leads to inhibition of Ras activation, downregulation of MAPK activity, and reduced function of PLCγ and PKC, ultimately decreasing cell activation, proliferation, and survival. On B cells specifically, FcγRIIb raises the activation threshold for the B cell receptor (BCR), suppresses antigen presentation to T cells, downregulates antibody production, and can promote apoptosis[1]. On follicular dendritic cells, FcγRIIb is essential for capturing antigen-containing immune complexes necessary for germinal center responses. Without FcγRIIb on these cells, germinal centers become more diverse but are populated by lower affinity B cells with reduced somatic hypermutation[1]. The receptor is also expressed on non-leukocyte cells including airway smooth muscle and liver sinusoidal endothelial cells, where it mediates internalization of small immune complexes and inhibits pro-inflammatory signaling[1]. Multiple epidemiological studies have linked polymorphisms in the transmembrane domain of FcγRIIb to autoimmune diseases, and mutagenesis studies confirm that alterations in this region impair the receptor's ability to attenuate B cell signaling[1]. Expression of FcγRIIb is positively regulated by IL-10 and IL-6, and negatively regulated by TNF-α, C5a, and IFN-γ[1].

Other names

FCGR2BCD32CD32bFc gamma receptor IIbFcγRIIbFcgRIIbFc gamma RIIFcγRII

Inhibition of activating Fc gamma receptors through ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif) signaling; Recruitment of inositol phosphatases (SHIP1 and SHIP2); Downregulation of MAPK activity; Inhibition of Ras activation; Competition with activating FcγRs for immune complex binding