The plasma protein properdin was discovered more than a half-century ago in connection with the alternative pathway (AP) of complement activation. Although it was initially regarded as an initiator of the AP complement, the currently held view of properdin function is that it acts as a stabilizer of the AP C3 convertase C3bBb, playing a facilitating but not essential role in AP complement activation. We have generated preliminary data to show that properdin is critical for AP complement activation on autologous tissues, thus challenging the present view on properdin function and identifying it as a potential therapeutic target in complement injury. In this proposal, we will define the role of properdin in AP complement activation and tissue injury and explore the strategy of anti-properdin therapy in murine models of complement-dependent disease.
Our specific aims are: 1. To generate tissue-specific properdin knockout mice and anti-mouse properdin antibodies and determine the source and turnover of properdin in vivo. 2. To test the role of properdin in murine models of arthritis and evaluate the efficacy of anti-properdin therapy in arthritis;3.To test the role of properdin in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and evaluate the efficacy of anti-properdin therapy in aHUS. These studies will shed new light on the role and mechanism action of properdin and facilitate the development of novel anti-complement therapies for arthritis, aHUS and other AP complement-mediated pathologies.

Public Health Relevance

This project studies the role of a protein called properdin in two immune-mediated diseases affecting the joints (arthritis) and the kidney (aHUS, for atypical hemolytic uremic syndrome). We will use the mouse as a model to test the hypothesis that properdin is involved in the pathogenesis of arthritis and aHUS and will develop monoclonal antibodies against properdin to treat these two diseases. These pre-clinical studies may lead to the development of anti-properdin agents as therapeutic drugs for human patients suffering from these conditions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-H (02))
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Nasseri, M Faraz
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University of Pennsylvania
Schools of Medicine
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Miao, Jing; Lesher, Allison M; Miwa, Takashi et al. (2014) Tissue-specific deletion of Crry from mouse proximal tubular epithelial cells increases susceptibility to renal ischemia-reperfusion injury. Kidney Int 86:726-37
Zhang, Congcong; Li, Yulin; Wang, Chunxiao et al. (2014) Complement 5a receptor mediates angiotensin II-induced cardiac inflammation and remodeling. Arterioscler Thromb Vasc Biol 34:1240-8
Miwa, Takashi; Sato, Sayaka; Gullipalli, Damodar et al. (2013) Blocking properdin, the alternative pathway, and anaphylatoxin receptors ameliorates renal ischemia-reperfusion injury in decay-accelerating factor and CD59 double-knockout mice. J Immunol 190:3552-9
Ruseva, Marieta M; Vernon, Katherine A; Lesher, Allison M et al. (2013) Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency. J Am Soc Nephrol 24:43-52
Lesher, Allison M; Zhou, Lin; Kimura, Yuko et al. (2013) Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis. J Am Soc Nephrol 24:53-65
Lesher, Allison M; Nilsson, Bo; Song, Wen-Chao (2013) Properdin in complement activation and tissue injury. Mol Immunol 56:191-8
Gauvreau, Danny; Roy, Christian; Tom, Fun-Qun et al. (2012) A new effector of lipid metabolism: complement factor properdin. Mol Immunol 51:73-81
Song, Wen-Chao (2012) Crosstalk between complement and toll-like receptors. Toxicol Pathol 40:174-82
Zhou, Hui-Fang; Yan, Huimin; Stover, Cordula M et al. (2012) Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm. Proc Natl Acad Sci U S A 109:E415-22
Dunkelberger, Jason R; Song, Wen-Chao (2010) Role and mechanism of action of complement in regulating T cell immunity. Mol Immunol 47:2176-86

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