FcRIIb

Fc gamma receptor IIb (FcγRIIb) is the inhibitory member of the classical Fc gamma receptor family. It binds the Fc portion of IgG antibodies and is encoded by the FCGR2B gene. The receptor is mainly expressed on B cells and on certain myeloid and dendritic cell populations. It functions as a negative regulator of immune activation by dampening signaling through the B cell receptor and other activating receptors on the same cell.

Molecularly, FcγRIIb is a type I membrane protein with two extracellular Ig-like domains and a cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM). When FcγRIIb is co-engaged with Fc receptors or the BCR by immune complexes, the ITIM is phosphorylated and recruits phosphatases such as SHIP-1 and SHP-1, antagonizing kinases that drive activation. This inhibitory signal helps set thresholds for B cell activation and promotes tolerance.

Expression and function: In B cells, FcγRIIb modulates activation, differentiation, and antibody production; it is also present on monocytes, basophils, eosinophils, and dendritic cells, where it can decrease inflammatory responses to IgG-coated stimuli. Engagement by immune complexes or therapeutic IVIG can contribute to anti-inflammatory effects. Defects or reduced expression of FcγRIIb can predispose to autoimmunity by allowing excessive B cell activity and autoantibody generation.

Genetics and disease relevance: The FCGR2B gene shows polymorphisms, including the I232T substitution in the transmembrane region, which impairs surface expression and inhibitory signaling and has been associated with increased risk of systemic lupus erythematosus and other autoimmune diseases. Differences in receptor density among individuals and cell types can influence responses to antibodies and biologic therapies.

Clinical and therapeutic considerations: Modulation of FcγRIIb signaling is being explored to tune immune responses and improve safety in antibody therapies. Understanding FcγRIIb function helps explain variability in IVIG efficacy and autoimmune disease pathogenesis.