IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses

Intravenous immunoglobulin (IVIg) has been used in the treatment of several autoimmune and inflammatory diseases. However, its mechanism of action remains incompletely understood. Here, we investigated the possibility that IVIg induces its anti-inflammatory effects through activating Fc gamma receptors bearing an immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma signaling adaptor. Recently, the concept of inhibitory ITAM (ITAMi) has emerged as a new means to negatively control the immune response. We found that interaction of FcR gamma-associated mouse or human Fc gamma RIII with uncomplexed IgG1 or IVIg, or with bivalent anti-Fc gamma RIII F(ab')(2) reduced calcium responses, reactive oxygen species production, endocytosis, and phagocytosis, induced by heterologous activating receptors on monocyte/macrophages and Fc gamma RIII+ transfectants. Inhibition required the ITAMi configuration of the Fc gamma RIII-associated FcR gamma subunit and SHP-1 recruitment involving formation of intracellular inhibisome clusters containing Fc gamma RIII, and the targeted heterologous activating receptor. IVIg as well as anti-Fc gamma RIII treatments controlled the development of nonimmune mediated inflammation in vivo independently of Fc gamma RIIB. These results demonstrate that circulating immunoglobulins (Ig) Gs are not functionally inert but act through continuous interaction with Fc gamma RIII-inducing ITAMi signaling to maintain immune homeostasis. These data support a new mechanism of action for IVIg and demonstrate the therapeutic potential of Fc gamma RIIIA targeting in inflammation. (Blood. 2012;119(13):3084-3096)