The complement system is a major player in innate immunity and an effector arm of the humoral immune response. Through natural Abs, lectins and the alternative pathway (AP), especially the AP's feedback loop, the complement system activates on microbes and altered self. Injured, apoptotic and necrotic cells, accumulations of debris, and microbial pathogens are targets. As we age, lipids deposit in blood vessel walls (atherosclerosis), urate in joints (gout), amyloid proteins in the brain (Alzheimer's disease - AD) and lipofuscin pigments (drusen) in the retina (age-related macular degeneration - AMD). These body """"""""wastes"""""""" or """"""""garbage"""""""" become substrates for complement activation, leading to chronic inflammation. Thus, regulation of the complement system, particularly the amplification loop, is critical to immune homeostasis and to prevent undesirable activation in vital organs. The goal of this grant proposal is to build on prior contributions relating to interactions of the complement's key C3b fragment with receptors and regulators and to further explore its role as a nidus for assembling the feedback loop by: 1) assessing C3b interactions with its regulators and receptors, with a goal of characterizing novel heterozygous mutations in C3 that predispose to atypical hemolytic uremic syndrome (aHUS) and on a polymorphism in C3 associated with age-related macular degeneration and renal transplant survival;2) further defining the structure and function of complement receptor type one (CR1;CD35), including analyzing recently identified mutations associated with human disease;and 3) employing a newly generated animal model, the Crry-single knockout (SKO) mouse, and the Crry mouse to examine complement regulation in vivo with a focus on homeostasis of the AP's feedback loop and to assess models of human disease in which the AP mediates pathologic consequences. An underlying hypothesis for proposed experiments is that the AP is continuously turning over on cells and thereby serves as a surveillance system for foreign agents and altered self.

Public Health Relevance

The innate immune system responds to microorganisms and damaged host tissue. It is involved in many common human diseases featuring deposition of altered proteins in the brain (Alzheimer Disease), lipids in vessel walls (heart attacks and strokes) and pigments in the retina (age-related macular degeneration). Chronic inflammation in such vital organs is undesirable. Also, many pathogens including the malarial parasite, a major health risk for much of the world, take advantage of innate immune players to invade, infect, and injure. These studies will enhance our understanding of how the innate immune system participates in some of the most common and lethal diseases of man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041592-15
Application #
8423312
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Nasseri, M Faraz
Project Start
1997-07-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
15
Fiscal Year
2013
Total Cost
$350,092
Indirect Cost
$119,768
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lintner, Katherine E; Wu, Yee Ling; Yang, Yan et al. (2016) Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 7:36
Wagner, Erin K; Raychaudhuri, Soumya; Villalonga, Mercedes B et al. (2016) Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci Rep 6:31531
Lyzogubov, Valeriy V; Bora, Puran S; Wu, Xiaobo et al. (2016) The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype. Am J Pathol 186:2088-104
Elvington, Michelle; Liszewski, M Kathryn; Atkinson, John P (2016) Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev 274:9-15
Fonseca, Maria I; Chu, Shuhui; Pierce, Aimee L et al. (2016) Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function. PLoS One 11:e0149792
Triebwasser, Michael P; Roberson, Elisha D O; Yu, Yi et al. (2015) Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 56:6873-8
Kavanagh, David; Yu, Yi; Schramm, Elizabeth C et al. (2015) Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum Mol Genet 24:3861-70
Lyzogubov, Valeriy; Wu, Xiaobo; Jha, Purushottam et al. (2014) Complement regulatory protein CD46 protects against choroidal neovascularization in mice. Am J Pathol 184:2537-48
Pinto, Amelia K; Ramos, Hilario J; Wu, Xiaobo et al. (2014) Deficient IFN signaling by myeloid cells leads to MAVS-dependent virus-induced sepsis. PLoS Pathog 10:e1004086
Yu, Yi; Triebwasser, Michael P; Wong, Edwin K S et al. (2014) Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Genet 23:5283-93

Showing the most recent 10 out of 44 publications