The specific aims of the research proposed here are to describe in detail the chemical mechanism for covalent bond formation between both the third (C3) and the fourth (C4) human complement proteins and the variety of molecules with which they can form either acyl ester or amide bonds and to determine the chemical nature of interactions between these proteins and antigen and antibody molecules. The activation of C3 and C4 and their subsequent covalent binding to immune complexes are key steps in the processing and clearance of the complexes. Hence, the chemical reactivity of these complement proteins with antigen and antibody molecules is of special concern, particularly in view of the finding that genetically different forms of C3 and C4 are known to be associated with certain auto-immune diseases of which systemic lupus erythematosus is an example. Indeed, in view of our current knowledge of the chemical and molecular properties of C3 and C4 it is appropriate at this time to focus our attention on their interactions with antigen and antibody molecules in relation to immune complex-mediated disease in general. Accordingly, we will investigate 1) the mechanism of covalent bond formation and hydrolysis, 2) the chemical nature of covalent bonds formed between C3 and C4 and model immune complexes composed of ovalbumin and anti-ovalbumin, 3) the covalent interactions between C3 and C4 and DNA antigens, 4) the covalent interactions between C3 and C4 and the capsular polysaccharide antigen of Haemophilus influenzae, type b, and 5) the use of anti-C4 monoclonal antibodies as probes of C4 structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI016543-09
Application #
3126701
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-03-01
Project End
1991-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jarvis, J N; Lockman, J C; Levine, R P (1993) IgM rheumatoid factor and the inhibition of covalent binding of C4b to IgG in immune complexes. Clin Exp Rheumatol 11:135-41
Cates, K L; Densen, P; Lockman, J C et al. (1992) C4B deficiency is not associated with meningitis or bacteremia with encapsulated bacteria. J Infect Dis 165:942-4
Cates, K L; Lockman, J; Densen, P et al. (1992) Interactions of C3 and C4 with Haemophilus influenzae. J Infect Dis 165 Suppl 1:S70-1
Venkatesh, Y P; Levine, R P (1988) The esterase-like activity of covalently bound human third complement protein. Mol Immunol 25:821-8
Kishore, N; Shah, D; Skanes, V M et al. (1988) The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins. Mol Immunol 25:811-9
Kemp, M E; Atkinson, J P; Skanes, V M et al. (1987) Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis Rheum 30:1015-22
Weis, J J; Law, S K; Levine, R P et al. (1985) Resistance to phagocytosis by group A streptococci: failure of deposited complement opsonins to interact with cellular receptors. J Immunol 134:500-5