Primary roles for human neutrophil Fc receptors in the initiation of nephrotoxic glomerulonephritis

Antibody‐antigen complexes promote inflammatory and autoimmune diseases. Mice deficient in γ‐chain of Fc‐receptors are protected in antibody mediated glomerulonephritis and lupus nephritis and FcR‐bearing macrophages have been implicated as the primary initiators of disease. However, how well studies of diseases mediated by murine receptors accurately reflect human inflammation remains unclear. Here we show that neutrophil selective transgenic expression of the two uniquely human FcγRIIA and FcγRIIIB in γ‐chain deficient mice (IIA+IIIBtg/γ −/− ) was sufficient to promote progressive glomerulonephritis associated with glomerular neutrophil accumulation, glomerulosclerosis, macrophage and T cell accumulation, renal failure and mortality. These responses far exceeded those in wild‐type mice despite similar expression levels of activating receptors suggesting that the human and mouse FcγRs are not functionally equivalent. Both FcγRIIIB and FcγRIIA promoted robust neutrophil recruitment while FcγRIIA alone mediated tissue injury. The latter was consistent with the robust adhesion dependent H 2 O 2 production in IIAtg/γ −/− and the lack there of in IIIBtg/γ −/ − . Thus, human neutrophil FcγRs serve as molecular links between immune complexes and renal injury suggesting a new paradigm for FcγRs on neutrophils in the initiation of antibody mediated‐glomerulonephritis. Funded by HL065095 , AR050800 and Arthritis Foundation Postdoctoral Fellowship.