2015 Distinguished Innovator Awardee
IgG glycans, FcgRs and renal elements dictate antibody pathogenicity in SLE
The Study and What It Means to Patients
“Why do some patients develop lupus nephritis while others never do? Our research will shed light on why and how inflammation in the kidneys is triggered and will provide a basis for new preventative treatments.”
Lupus occurs when antibodies called autoantibodies deposit in tissues and serve as a stimulus for the white blood cells of your body to mistakenly attack the body’s own healthy cells or tissues. In 30 to 60 percent of lupus patients, autoantibodies will accumulate in the kidneys causing lupus nephritis, one of the most severe manifestations of lupus that causes inflammation in the organ and can lead to kidney failure. However, autoantibody deposits do not necessarily induce kidney inflammation. We propose to identify those characteristics that make certain autoantibodies more likely to cause lupus nephritis. We will specifically research why and how autoantibodies accumulate in some lupus patients but not others, and determine the autoantibody characteristics that promote white blood cell accumulation thus providing a basis for therapies designed to prevent kidney disease.
Circulating autoantibodies are a hallmark of lupus but are not sufficient for clinical disease. This is highlighted by the finding that elevated levels of autoantibodies are found in first-degree relatives that don’t develop disease. Similar conclusions are reached in mouse models of lupus including 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 (hFcRs) on neutrophils cause glomerulonephritis only when the mice additionally lack the leukocyte complement receptor, Mac-1. This result may be clinically relevant as an identified non-synonymous Mac-1 polymorphism that increases lupus risk reduces Mac-1 function. FcR activity is fundamentally controlled by IgG glycosylation and IgG from active SLE patients have altered glycosylation patterns. 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 FcRs and complement receptors execute kidney inflammation. Moreover, we propose that local IgG-FcR mediated neutrophil activation 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 FcRs and glomerulonephritis (T. Mayadas) and IgG-glycobiology (R. Anthony).