Circulating autoantibodies are a hallmark of lupus but are not sufficient for clinical disease. This is highlighted in our novel murine lupus nephritis model induced by the passive transfer of human SLE sera: Human IgG-immune-complexes deposited in the kidney of mice expressing uniquely human IgG receptors (hFcgRs) on neutrophils. However, they caused glomerulonephritis only in mice that additionally lacked the leukocyte complement receptor, Mac-1 suggesting that Mac-1 restrains FcgR activity(1), a finding that may be clinically relevant(2-5). FcgR activity is fundamentally controlled by IgG glycosylation(6,7) and IgG from active SLE patients have altered glycosylation patterns(8). Here, we will test the hypothesis that distinct glycosylation patterns of IgG in SLE in concert with a particular combination of expression of neutrophil human FcgRs and complement receptors execute kidney inflammation. Moreover, we propose that local IgG-FcgR mediated neutrophil activation destroys the glycocalyx, a protective carbohydrate-rich layer covering the luminal aspect of the glomerular endothelium. This, we predict, promotes subendothelial deposition of immune-complexes that perpetuates inflammation. We will test these hypotheses using our humanized lupus nephritis model and cutting-edge techniques to characterize and manipulate IgG glycosylation, which will be enabled by our complimentary expertise in neutrophil FcgRs and glomerulonephritis (T.Mayadas) and IgG-glycobiology (R.Anthony).