The complement system is a complex group of proteins and glycoproteins, which together play an important role in host defense against infection. Complement can be activated by three distinct pathways, the classical (antibody-dependent), the alternative and the lectin pathway. Activated complement generates pro-inflammatory peptide mediators (C3a and C5a) and a cytolytic membrane attack complex (C5b-9). By its indiscriminative nature, complement has the potential to cause significant damage to self-tissues. This is particularly true in an autoimmune disease setting where autoantibodies are produced and immune complexes are deposited in vital organs such as the kidney with subsequent activation of the classical pathway. Thus, complement activation is well established to be a major effector pathway in autoantibody-mediated inflammatory injury in immune glomerulonephritis. So far, however, the parameters that determine complement susceptibility in immune glomerulonephritis have not been clearly defined. In this project, we will address the overall hypothesis that membrane-anchored regulators of complement activation, either acting at the C3 cleavage step or at the C5b-9 assembly step, are critical parameters of complement-mediated injury in immune glomerulonephritis. Our approach is to use knockout mouse lines deficient in complement regulators and determine their susceptibility to anti-glomerulus basement membrane (GBM)-induced glomerulonephritis.
Our specific aims are: (1) to test the hypothesis that mice deficient in the terminal complement regulator CD59 are more susceptible to anti-GBM glomerulonephritis; (2) To test the hypothesis that there is overlap and synergy between different complement regulators such that mice deficient in two C3 regulators (DAF and Crry), and mice deficient in a C3 regulator (DAF) and the terminal regulator (CD59) sustain more injury than mice deficient in a single regulator; (3) to test the hypothesis that the increased disease susceptibility of complement regulator-deficient mice can be ameliorated by administration of recombinant soluble C3 regulators (DAF or Crry). These studies will increase our understanding of the pathogenesis of complement-mediatedautoimmune injury and facilitate the development of complement-based therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI049344-01A1
Application #
6435238
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ridge, John P
Project Start
2002-03-01
Project End
2007-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
1
Fiscal Year
2002
Total Cost
$132,083
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Williams, Allison Lesher; Gullipalli, Damodar; Ueda, Yoshiyasu et al. (2017) C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy. Kidney Int 91:1386-1397
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
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
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
Barata, Lidia; Miwa, Takashi; Sato, Sayaka et al. (2013) Deletion of Crry and DAF on murine platelets stimulates thrombopoiesis and increases factor H-dependent resistance of peripheral platelets to complement attack. J Immunol 190:2886-95
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
Song, Wen-Chao (2012) Crosstalk between complement and toll-like receptors. Toxicol Pathol 40:174-82
Dunkelberger, Jason; Zhou, Lin; Miwa, Takashi et al. (2012) C5aR expression in a novel GFP reporter gene knockin mouse: implications for the mechanism of action of C5aR signaling in T cell immunity. J Immunol 188:4032-42
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

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