Primary role for human neutrophil FcγRIIA and C5aR in the development of inflammatory rheumatoid arthritis

Deposition of antigen‐antibody complexes in tissues is a hallmark of autoimmune diseases such as rheumatoid arthritis. Mice lacking FcγRs for complexed IgG (γ‐chain deficient, γ −/− ) or complement components are protected from developing arthritis and mast cells and vascular permeability are required for disease. However, these studies may not fully reflect human inflammation as mouse and human FcγRs structurally differ. Here we show that neutrophil‐selective transgenic expression of the uniquely human FcγRIIA in γ −/− mice was sufficient to restore susceptibility to K/BxN serum induced arthritis. FcγRIIAtg/γ−/− mice exhibited robust neutrophil accumulation, ankle swelling and bone erosion while γ −/− mice remained resistant. Arthritis in FcγRIIAtg/γ −/− was observed in the absence of joint edema and was also evident in the context of mast cell deficiency. Thus mast cells and joint permeability were not essential for disease development. C5aR antagonist or C3 depletion significantly reduced disease indices in transgenic animals. In vitro, complement C5a stimulation of neutrophils enhanced FcγRIIA mediated binding of complexed IgG. Thus human neutrophil FcγRIIA coupled with C5aR are sufficient to promote joint injury in a model that has relevance for human disease. In addition, our results provide a possible mechanism of cross‐talk between FcγRs and complement, two important immune effector pathways.