Complement is a part of innate immunity and plays a key role in host defense. However, if not properly regulated, activated complement can cause inflammatory injury. Recent works have identified complement as a major pathogenic pathway in many human immunological and inflammatory diseases. Among them, dense deposit disease (DDD) is a rare kidney disease caused by dysregulation of the alternative pathway (AP) of complement activation. DDD is characterized by the presence of electron- dense deposits within the glomerular basement membrane of the kidney. Known also as membranoproliferative glomerulonephritis type II (MPGN type II), DDD belongs to the recently introduced pathological entity called C3 glomerulopathy whose definition is glomerular pathology characterized by C3 accumulation with no or limited immunoglobulin deposition. Approximately 10% of DDD patients also develop vision problems with dense deposits underneath retinal pigment epithelial cells that resemble drusen deposits in the eyes of age-related macular degeneration patients. Prognosis of DDD is poor since current treatments are largely nonspecific and about 50% patients eventually progress to end stage renal failure. Mechanistic and therapeutic studies of human DDD have been hampered by the lack of appropriate animal models. We have recently generated a robust mouse model of DDD displaying both kidney and retinal pathologies. The objective of this application is to use this novel mouse model to investigate the pathogenic mechanisms of complement-mediated kidney and retinal injury in DDD and to test the activity of various anti-complement agents in preventing or reversing the kidney and eye pathologies. Our long term goal is to better understand how dysregulated AP complement leads to DDD and other complement-mediated inflammatory disorders and to provide proof of principle for developing novel anti-complement therapies for such human diseases.

Public Health Relevance

This project uses a mouse model to study what causes and how to treat a rare human disease called dense deposit disease (DDD). Patients with DDD often develop kidney failure and vision loss and currently no treatment is available. The proposed studies will help the development of highly specific and effective drugs for these patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Liu, Qian
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University of Pennsylvania
Schools of Medicine
United States
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