Although complement plays an essential role in host defense, activated complement is a double-edged sword that has the potential to inflict substantial damage to self-tissues. One type of pathological conditions under which such complement-mediated damage has been widely assumed to occur is autoimmune disease. Recent works using complement- and Fc receptor-deficient mice, however, have challenged this widely held belief and cast doubt on the relevance of complement in autoimmune disease pathogenesis. As mammalian cells are usually well protected by membrane-bound complement regulatory proteins, we hypothesize that complement regulatory proteins represent important variables in determining the degree of complement involvement in the pathogenesis of autoimmune diseases. In this study, we will test this hypothesis in two well-established autoimmune disease models by using mice that are deficient in one or two central membrane complement regulatory proteins, namely decay-accelerating factor (DAF) and Crry. DAF/Crry and DAF/Fc receptor (FcR) double knockout mice will be generated by cross breeding DAF knockout mice with Crry knockout or FcR knockout mice, respectively. These mice, as well as the relevant single knockout and wild-type mice, will be used in the immune hemolytic anemia and anti-GBM-glomerulonephritis disease models to dissect the relative roles of complement, the FcR pathway, and membrane complement regulators in autoimmune disease pathogenesis.
The specific aims are: 1) to generate DAF/Crry, and DAF/FcR double-deficient mice by cross breeding; 2) To determine if autoimmune hemolytic anemia is exacerbated in mice which lack DAF or DAF/Crry; 3) To determine if anti-GBM-glomerulonephritis is exacerbated in mice which lack DAF or DAF/Crry. These studies will test the in vivo function of membrane complement regulators and will help resolve the ongoing controversy regarding the role of complement in autoimmune disease pathogenesis. A better understanding of these issues will have direct therapeutic implications for human autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI049344-01
Application #
6317608
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Collier, Elaine S
Project Start
2001-09-30
Project End
2002-09-29
Budget Start
2001-09-30
Budget End
2002-09-29
Support Year
1
Fiscal Year
2001
Total Cost
$302,375
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
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
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

Showing the most recent 10 out of 15 publications