Complement (C) plays an important role in host defense; however, activated C is a double-edged sword that has the potential to cause significant damage to host tissues. To prevent C-mediated autologous injury, host cells express a number of C regulatory proteins on their surface. Among such molecules are two GPI anchored proteins: DAF and CD59, which inhibit C activation at the C3 cleavage and membrane attack complex (MAC) assembly step, respectively. DAP and CD59 may also regulate adaptive immunity through C-independent mechanisms. For example, GPI-anchored molecules like DAP and CD59 may participate in lymphocyte signaling as lipid rafts components and DAF has been identified as a ligand for an activation associated lymphocyte receptor CD97. In our preliminary studies using MRL/lpr mice, a murine model of systemic lupus erythematosus (SLE), we have found that DAP-/- and CD59-/- MRL/Ipr mice developed exacerbated skin disease and increased lymphoproliferation and autoantibody production. The overall objective of this proposal is to elucidate the protective mechanisms of DAF and CD59 in MRL/Ipr mice. Our hypothesis is that DAF and CD59 regulate SLE both at the inductive and effector phases of the disease. We further postulate that the role of DAF and CD59 in the effector phase of SLE is C-dependent, whereas their role in the inductive phase of the disease is C-independent.
Our aims are: 1). To dissect the C-dependent and independent functions of DAE and CD59 in MRL/lpr mice. 2). To dissect the local versus the systemic effect of DAF and CD59 in MRL/lpr mice. 3).To uncover the specific C mediators (C3a, C5a or MAC) responsible for end organ injury in MRL/lpr-DAF-/- and MRL/lpr-CD59-/- mice. 4). To determine if the protective effect of DAE and CD59 is specific to the MRL/lpr mouse strain. Results of this proposal will shed new light on the pathogenesis of SLE and may reveal novel regulatory functions of DAF and CD59 in adaptive immunity. Such results should facilitate the development of innovative therapeutic strategies for human SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI063288-01
Application #
6855241
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2004-12-15
Project End
2009-11-30
Budget Start
2004-12-15
Budget End
2005-11-30
Support Year
1
Fiscal Year
2005
Total Cost
$396,250
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Miwa, Takashi; Zhou, Lin; Maldonado, Michael A et al. (2012) Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice. J Immunol 189:5434-41
Fang, Chongyun; Miwa, Takashi; Song, Wen-Chao (2011) Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen-presenting cells. Blood 118:1008-14
Dunkelberger, Jason R; Song, Wen-Chao (2010) Role and mechanism of action of complement in regulating T cell immunity. Mol Immunol 47:2176-86
Kimura, Yuko; Zhou, Lin; Miwa, Takashi et al. (2010) Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury. J Clin Invest 120:3545-54
Toomey, Christopher B; Cauvi, David M; Song, Wen-Chao et al. (2010) Decay-accelerating factor 1 (Daf1) deficiency exacerbates xenobiotic-induced autoimmunity. Immunology 131:99-106
Lesher, Allison M; Song, Wen-Chao (2010) Review: Complement and its regulatory proteins in kidney diseases. Nephrology (Carlton) 15:663-75
Bao, Lihua; Haas, Mark; Pippin, Jeffrey et al. (2009) Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells. J Clin Invest 119:1264-74
An, Guipeng; Miwa, Takashi; Song, Wen-Liang et al. (2009) CD59 but not DAF deficiency accelerates atherosclerosis in female ApoE knockout mice. Mol Immunol 46:1702-9
Miwa, Takashi; Zhou, Lin; Kimura, Yuko et al. (2009) Complement-dependent T-cell lymphopenia caused by thymocyte deletion of the membrane complement regulator Crry. Blood 113:2684-94

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