| First Author | Aloulou M | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 13 | Pages | 3084-96 |
| PubMed ID | 22337713 | Mgi Jnum | J:182509 |
| Mgi Id | MGI:5315785 | Doi | 10.1182/blood-2011-08-376046 |
| Citation | Aloulou M, et al. (2012) IgG1 and IVIg induce inhibitory ITAM signaling through FcgammaRIII controlling inflammatory responses. Blood 119(13):3084-96 |
| abstractText | 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 Fcgamma receptors bearing an immunoreceptor tyrosine-based activation motif (ITAM) in the FcRgamma 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 FcRgamma-associated mouse or human FcgammaRIII with uncomplexed IgG1 or IVIg, or with bivalent anti-FcgammaRIII F(ab')(2) reduced calcium responses, reactive oxygen species production, endocytosis, and phagocytosis, induced by heterologous activating receptors on monocyte/macrophages and FcgammaRIII(+) transfectants. Inhibition required the ITAMi configuration of the FcgammaRIII-associated FcRgamma subunit and SHP-1 recruitment involving formation of intracellular "inhibisome" clusters containing FcgammaRIII, and the targeted heterologous activating receptor. IVIg as well as anti-FcgammaRIII treatments controlled the development of nonimmune mediated inflammation in vivo independently of FcgammaRIIB. These results demonstrate that circulating immunoglobulins (Ig)Gs are not functionally inert but act through continuous interaction with FcgammaRIII-inducing ITAMi signaling to maintain immune homeostasis. These data support a new mechanism of action for IVIg and demonstrate the therapeutic potential of FcgammaRIIIA targeting in inflammation. |
