Human neutrophil Fc gamma receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases

Inflammation mediated by anti body-antigen complexes contributes to autoimmune diseases. Mice deficient in the common Fc gamma-chain are protected from IgG-mediated glomerulonephritis and the reverse passive Arthus (RPA) reaction and FcR-bearing macrophages, and mast cells have been assigned primary roles in these processes. Here we demonstrate that neutrophil-selective transgenic expression of the two uniquely human neutrophil Fc gamma receptors (Fc gamma Rs), Fc gamma RIIA and Fc gamma RIIIB, in Fc gamma-chain-deficient mice restored susceptibility to progressive glomerulonephritis and the cutaneous RPA reaction. Fc gamma RIIIB and Fc gamma RIIA mediated neutrophil accumulation, whereas Fc gamma RIIA alone promoted organ injury. In a model of soluble immune complexes deposited within the vasculature, Fc gamma RIIIB was responsible for neutrophil slow rolling and adhesion whereas in the cremaster RPA, induced by both vascular and tissue soluble immune complexes, Fc gamma RIIA predominated. Thus, human Fc gamma Rs on neutrophils serve as molecular links between antibody and immunological disease, with Fc gamma RIIA promoting tissue injury and Fc gamma RIIIB and Fc gamma RIIA displaying specialized context-dependent functions in neutrophil recruitment.