Pathogenesis and therapy of complement-mediated kidney disease in a mouse model

Allison M Lesher, University of Pennsylvania


The complement system is a branch of innate immunity tasked with aiding in the recognition and elimination of pathogens from the host. It is a crucial component of the first-line of defense but its powerful effects must be carefully regulated to protect autologous cells from bystander injury. Compromises in complement regulation, especially of the continuously active alternative pathway (AP), have been associated with a number of autoimmune and inflammatory human diseases. In particular, dysfunction of the circulating AP inhibitor factor H (fH) has been linked to several renal diseases including C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and atypical hemolytic uremic syndrome. While these diseases are rare, patient prognosis is poor and current treatments are nonspecific and largely ineffective. A potential therapeutic target is factor properdin (fP), the only known positive regulator of AP complement. Previous studies have demonstrated that inhibition of fP can effectively ameliorate AP complement-mediated disease in mouse models of rheumatoid arthritis and fetal development, which suggests its potential use in other disease settings. In this work, we generate a novel model of C3GN by engineering a mutant fH mouse line (fHm/m) through gene targeting. Surprisingly, loss of fP function in fHm/m mice did not limit disease, but instead accelerated renal injury to produce a fatal C3GN phenotype resembling human DDD. We performed mechanistic studies to understand and explain this unexpected result. We further used this novel mouse model to carry out therapeutic experiments. We found benefit from the inhibition of downstream complement activation in fHm/m/fP -/- mice by using an anti-C5 antibody. These results have high clinical significance as recent reports have also shown improvement in some C3GN and DDD patients from the off-label use of a humanized anti-C5 antibody, eculizumab. Additional studies examined the role of fP in other models of AP-mediated injury and demonstrated that fP inhibition was protective in settings of surface-mediated AP activation but was not essential in the fluid-phase. In summary, these studies have revealed novel insights on fP function and the pathogenesis of C3 glomerulopathy and we conclude that complement-based therapeutics hold great promise but require rigorous disease-specific target validation.

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Recommended Citation

Lesher, Allison M, "Pathogenesis and therapy of complement-mediated kidney disease in a mouse model" (2013). Dissertations available from ProQuest. AAI3565119.