IgG Fc Receptors

Abstract

Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating Fc gamma Rs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. Fc gamma Rs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.

The CD300a (IRp60) inhibitory receptor is rapidly up-regulated on human neutrophils in response to inflammatory stimuli and modulates CD32a (FcγRIIa) mediated signaling

“…To do this, we examined ROS production in response to co-ligation of CD300a with either CD32a (FcγRIIa) or TLR-4. Signaling mediated through CD32a (FcγRIIa) is dependent on the ITAM motif within its intracytoplasmic tail (Ravetch and Bolland, 2001), while TLR-4 signals are mediated through the MyD88 pathway (Fitzgerald and Chen, 2006). Figure 4A shows that ROS production in response to CD32a (FcγRIIa) aggregation with the IV.3 mAb is significantly inhibited if the activating CD32a (FcγRIIa) receptor and the inhibitory CD300a receptor are co-ligated.…”

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

“…Among the FcgRs, FcgRIIB plays a unique role in inducing inhibitory signals in B cells upon immune complex binding. 2 In humans, a À343 G/C promoter polymorphism and a Ile232Thr transmembrane polymorphism, both associated with loss of function, have been associated with lupus. 3 The strength of the association between each of these polymorphisms and disease varied among populations, most likely due to interactions with other susceptibility alleles segregating differently among these populations.…”

Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

“…In contrast, Fc␥RIIb can also generate a proapoptotic signal through its transmembrane segment upon homoaggregation of receptors (2,3). This apoptotic pathway may contribute to peripheral tolerance of B cells undergoing somatic hypermutation after antigens are retained as a noncognate immune complex in germinal center B cells (2,3,8).…”