IgG Fc receptors

Since the description of the first mouse knockout for an IgG Fc receptor se ven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of act ivating Fc gamma Rs in providing a critical link between ligands and effect or cells in type II and type III inflammation is now well established and h as 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. Consi derable progress has been made in the last two years on the in vivo regulat ion of these responses, through the appreciation of the importance of balan cing activation responses with inhibitory signaling. The inhibitory FcR fun ctions in the maintenance of peripheral tolerance, in regulating the thresh old of activation responses, and ultimately in terminating IgG mediated eff ector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune respons es. The hyperresponsive state that results leads to greatly magnified effec tor responses by cytotoxic antibodies and immune complexes and can culminat e in autoimmunity and autoimmune disease when modified by environmental or genetic factors. Fc gamma Rs offer a paradigm for the biological significan ce of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.