The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy

Receptors for the Fc portion of IgG (Fc gamma Rs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis, and cancer immunotherapy. A few Fc gamma Rs have the ability to bind monomeric IgG: high-affinity mouse mFc gamma RI, mFc gamma RIV, and human hFc gamma RI. All others bind IgG only when aggregated in complexes or bound to cells or surfaces: low-affinity mouse mFc gamma RIIB and mFc gamma RIII and human hFc gamma RIIA/B/C and hFc gamma RIIIA/B. Although it has been proposed that high-affinity Fc gamma Rs are occupied by circulating IgG, multiple roles for mFc gamma RI and mFc gamma RIV have been reported in vivo. However, the potential roles of hFc gamma RI that is expressed on monocytes, macrophages, and neutrophils have not been reported. In the present study, we therefore investigated the role of hFc gamma RI in antibody-mediated models of disease and therapy by generating hFc gamma RI-transgenic mice deficient for multiple endogenous FcRs. hFc gamma RI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, and active and passive systemic anaphylaxis. We found monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction. Finally, hFc gamma RI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Our results unravel novel capabilities of human Fc gamma RI that confirm the role of high-affinity IgG receptors in vivo.