STIM1 is essential for Fcγ receptor activation and autoimmune inflammation

Fc gamma receptors (Fc gamma Rs) 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. FcR gamma-based activation is critical in the pathogenesis of these diseases, although the contribution of Fc gamma R-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum resident calcium sensor, STIM1, cannot activate Fc gamma R-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 Fc gamma R activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases. (Blood. 2009;113:1097-1104)