STIM1 is essential for Fcreceptor activation and autoimmune inflammation

 Fc receptors (FcRs) on mononuclear phagocytes trigger autoantibody and immune complex–induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRbased activation is critical in the pathogenesis of these diseases, although the contribution of FcR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum– resident calcium sensor, STIM1, cannot activate FcR-induced Ca2 entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcR activation and also indicate that inhibition of STIM1dependent signaling might become a new strategy to prevent or treat IgGdependent immunologic diseases. (Blood. 2009;113:1097-1104)