Amelioration of Lupus Nephritis by Serum Amyloid P Component Gene Therapy with Distinct Mechanisms Varied from Different Stage of the Disease Weijuan Zhang1., Jin Wu1., Bin Qiao1, Wei Xu1, Sidong Xiong1,2* 1 Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China, 2 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, People’s Republic of China Abstract Background: Our previous study revealed that administration of syngeneic female BALB/c mice with excessive self activated lymphocyte-derived DNA (ALD-DNA) could induce systemic lupus erythematosus (SLE) disease, indicating that overload of self-DNA might exceed normal clearance ability and comprise the major source of autoantigens in lupus mice. Serum amyloid P component (SAP), an acute-phase serum protein with binding reactivity to DNA in mice, was proved to promote the clearance of free DNA and prevent mice against self-antigen induced autoimmune response. It is reasonable to hypothesize that SAP treatment might contribute to alleviation of SLE disease, whereas its role in ALD-DNA-induced lupus nephritis is not fully understood. Methodology/Principal Findings: The ratios of SAP to DNA significantly decreased and were negatively correlated with the titers of anti-dsDNA antibodies in ALD-DNA-induced lupus mice, indicating SAP was relatively insufficient in lupus mice. Herein a pcDNA3-SAP plasmid (pSAP) was genetically constructed and intramuscularly injected into BALB/c mice. It was found that SAP protein purified from the serum of pSAP-treated mice bound efficiently to ALD-DNA and inhibited ALD- DNA-mediated innate immune response in vitro. Treatment of ALD-DNA-induced lupus mice with pSAP in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex (IC) deposition. Further administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis. This therapeutic effect of SAP was not only attributable to the decreased levels of anti-dsDNA autoantibodies, but also associated with the decreased infiltration of lymphocytes and the reduced production of inflammatory markers. Conclusion/Significance: These results suggest that SAP administration could effectively alleviated lupus nephritis via modulating anti-dsDNA antibody production and the inflammation followed IC deposition, and SAP-based intervening strategy may provide new approaches for treating SLE disease. Citation: Zhang W, Wu J, Qiao B, Xu W, Xiong S (2011) Amelioration of Lupus Nephritis by Serum Amyloid P Component Gene Therapy with Distinct Mechanisms Varied from Different Stage of the Disease. PLoS ONE 6(7): e22659. doi:10.1371/journal.pone.0022659 Editor: Pierre Bobe, Institut Jacques Monod, France Received May 3, 2011; Accepted June 27, 2011; Published July 25, 2011 Copyright: 2011 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants of National Natural Science Foundation of China (30890141, 30671952), Major State Basic Research Development Program of China (2007CB512401), Shanghai STC grant (10JC1401400, 07JC14004), Program for Outstanding Medical Academic Leader of Shanghai (LJ06011), Research Fellow Fund and Startup Fund for Young Backbone Scholars of Shanghai Medical College, Fudan University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: sdxiongfd@126.com . These authors contributed equally to this work. Introduction Defect in clearance of self nuclear antigen is the hallmark of systemic lupus erythematosus (SLE), an autoantibody-mediated chronic autoimmune disease characterized by the deposition of immune complexes and its followed inflammation that contribute to sever organ damage [1–3]. However, the precise means by which clearance of self antigen is inefficient in SLE remain obscure. Studies of both mice and humans suggest that SLE could arise from excessive production of self antigen released from unremoved apoptotic cells and impairment in the ability of macrophages to clear self antigen [4,5]. Our previous study revealed that the syngeneic female BALB/c mice immunized with activated lymphocyte-derived DNA (ALD- DNA) develop high titers of anti-dsDNA antibodies, immune complex (IC) deposition, proteinuria, and glomerular nephritis which closely resemble human SLE [6–8], thus being used as a model to investigate pathogenesis and potential new therapies for human disease. These findings indicate that ALD-DNA, which mimics large amount of self-DNA released from unremoved apoptotic lymphocytes in SLE patients, might serve as an important self-immunogen to trigger the autoimmune responses which eventually lead to the pathogenesis of SLE in the murine model. In addition to DNA overload in SLE, insufficiency of DNA clearance represents the other side of the coin [4]. Emerging studies reveal that serum amyloid P component (SAP) would be PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e22659