The third component of complement (C3) plays a central role in generating the biologically significant effects of the complement system. Not only does activation of C3 create cleavage products (e.g. C3a and C3b) which directly mediate defensive and inflammatory activities, but the larger cleavage prouct, C3b, forms part of the enzymes which activate C5-C9. Thus, C3 is also important in the generation of activities mediated by C5-C9. The identification of animals and humans with genetically determined deficiencies of individual components of complement has been valuable in generating knowledge about the genetics, biochemistry and biological significance of the complement system. Although a few humans with genetically determined C3 deficiency have been described, until recently no experimental animals with C3 deficiency had been identified. In 1981 we described a colony of dogs with a genetically determined total deficiency of C3. the following specific aims are uniquely suited to study in the C3-deficient dog and should provide important insight into selected aspects of the role of C3 in immunobiology: 1) We will characterize the renal disease in C3-deficient dogs in order to gain insight into the etiology and pathogenesis of the renal disease found in human patients with both inherited and acquired abnormalities in the complement system. 2) We will study the clearance of soluble immune complexes in C3 deficient dogs in order to gain insight into the role of C3 in the processing of immune complexes in vivo. 3) We will determine if C3-deficient dogs have normal antibody formation in order to clarify the role of C3 in antibody formation in vivo. 4) We will investigate the molecular basis for the C3 deficiency in C3-deficient dogs in order to gain insight into one possible molecular mechanisms for genetically determined C3 deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019278-07
Application #
3128645
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ameratunga, R; Winkelstein, J A; Brody, L et al. (1998) Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency. J Immunol 160:2824-30
Fasano, M B; Winkelstein, J A; LaRosa, T et al. (1992) A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype. J Clin Invest 90:1180-4
Winkelstein, J A; Moxon, E R (1992) The role of complement in the host's defense against Haemophilus influenzae. J Infect Dis 165 Suppl 1:S62-5
Swift, A J; Moxon, E R; Zwahlen, A et al. (1991) Complement-mediated serum activities against genetically defined capsular transformants of Haemophilus influenzae. Microb Pathog 10:261-9
Cork, L C; Morris, J M; Olson, J L et al. (1991) Membranoproliferative glomerulonephritis in dogs with a genetically determined deficiency of the third component of complement. Clin Immunol Immunopathol 60:455-70
Bando, K; Pillai, R; Cameron, D E et al. (1990) Leukocyte depletion ameliorates free radical-mediated lung injury after cardiopulmonary bypass. J Thorac Cardiovasc Surg 99:873-7
Leonard, L A; Strandberg, J D; Winkelstein, J A (1990) Complement-like activity in the sea star, Asterias forbesi. Dev Comp Immunol 14:19-30
Fasano, M B; Densen, P; McLean, R H et al. (1990) Prevalence of homozygous C4B deficiency in patients with deficiencies of terminal complement components and meningococcemia. J Infect Dis 162:1220-1
Litt, M R; Jeremy, R W; Weisman, H F et al. (1989) Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury. Circulation 80:1816-27
Rowe, P C; McLean, R H; Wood, R A et al. (1989) Association of homozygous C4B deficiency with bacterial meningitis. J Infect Dis 160:448-51

Showing the most recent 10 out of 21 publications