The Role of the Human Fc Receptor FcγRIIA in the Immune Clearance of Platelets: A Transgenic Mouse Model

Abstract

Abstract In humans, the Fc receptor for IgG, FcγRIIA, is expressed on macrophages and platelets and may play an important role in the pathophysiology of immune-mediated thrombocytopenia. Mice lack the genetic equivalent of human FcγRIIA. To better understand the role of FcγRIIA in vivo, FcγRIIA transgenic mice were generated and characterized. One transgenic mouse line expressed FcγRIIA on platelets and macrophages at levels equivalent to human cells, and cross-linking FcγRIIA on these platelets induced platelet aggregation. Immune-mediated thrombocytopenia in this transgenic line was studied using i.v. and i.p. administration of anti-mouse platelet Ab. In comparison with matched wild-type littermates that are negative for the FcγRIIA transgene, Ab-mediated thrombocytopenia was significantly more severe in the FcγRIIA transgenic mice. In contrast, FcR γ-chain knockout mice that lack functional expression of the Fc receptors FcγRI and FcγRIII on splenic macrophages did not demonstrate Ab-mediated thrombocytopenia. We generated FcγRIIA transgenic × FcR γ-chain knockout mice to examine the role of FcγRIIA in immune clearance in the absence of functional FcγRI and FcγRIII. In FcγRIIA transgenic × FcR γ-chain knockout mice, severe immune thrombocytopenia mediated by FcγRIIA was observed. These results demonstrate that FcγRIIA does not require the FcR γ-chain for expression or function in vivo. Furthermore, taken together, the data suggest that the human Fc receptor FcγRIIA plays a significant role in the immune clearance of platelets in vivo.