Jeffrey V. Ravetch
The Rockefeller University, New York, NY

Antibody Triggered Effector Pathways

Inhibitory Fc receptors for IgG are responsible for maintaining peripheral tolerance; animals deficient in these molecules develop spontaneous autoimmunity and autoimmune disease. This loss of tolerance to nuclear antigens is strain-specific, establishing a critical role for epistasis in this model of autoimmunity. FcRIIB interacts with other known susceptibility loci to modify autoimmune disease, such as Sle1, Yaa lpr and at least two recessive loci identified in the C57B/6 strain through F2 analysis. Conversely, deficiency of activation Fc receptors result in a protective phenotype, uncoupling autoimmunity from autoimmune disease. Mice susceptible to spontaneous or induced autoimmune disease are protected when the activation FcR is deleted from the appropriate genetic background, without altering the development of autoantibody and immune complex deposition. Autoimmune disease can also be uncoupled from autoantibody production by upregulation of inhibitory receptor function on effector cells. This situation has been demonstrated to occur in IVIG protection in a murine model of immune thrombocytopenia. IVIG infusion results in the induction of FcRIIB expression on splenic macrophages, thereby preventing their clearance by anti-platelet antibodies. Modulation of activation and inhibitory receptors, then, is a central mechanism for mediating antibody coupling to effector cells. Thus the potency of a cytotoxic anti-tumor antibody, for example, can be dramatically increased by removing the inhibitory pathway in vivo. Balancing of activation and inhibitory immunoreceptors is central to both the afferent and efferent arms of the immune response and plays a critical role in determining the development of autoimmune disease.