Activation of the complement system results in a selective and control fragmentation of the C4 and C3 molecules via the classical, or the classical and alternative pathways respectively. Interaction of fragments of these two molecules with antigen-antibody complexes and with surface receptors on different cell types serve to modulate complement-dependent functions. Although a great deal of knowledge has been accumulated on the alternative pathway, the same information relating to the classical pathway is less complete. This application proposes studies aimed primarily at delineating some structural and functional aspects of the proteins involved in the formation and some structural and functional aspects of the proteins involved in the formation and function of the classical pathway C3 convertase. Specifically, we plan to 1) Further characterize the major cleavage fragments of C4 produced during activation and inactivation of the molecule. The fragments will be isolated to homogeneity and subjected to chemical analysis. 2) Analysis of the conformational changes accompanying the enzymatic conversion and degradative inactivation of C4 by various methods. These studies will use differential surface labeling which will allow the identification of distinct regions of the molecule involved in these functional changes. 3) Investigation of the structural requirements for the interaction of the control proteins, C4-bp and I, with fluid phase and surface bound C4b. 4) The observation of an abnormal protein seen in humans serum under pathological conditions, C4 nephritic factor, has prompted studies to identify a protein in normal serum capable of stabilizing the C4b2a enzyme. The identification of this protein would complete the analogies to the formation, function and regulation of the classical and alternative C3 convertases. A second part of the application to which the above studies are of interest involves the activation of the complement system by IgA and IgM containing immune complexes. In addition, the mechanisms of complement activation by a non-immunologic mechanism using phototoxic chemicals will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020067-05
Application #
3129583
Study Section
Experimental Immunology Study Section (EI)
Project Start
1982-09-15
Project End
1989-06-30
Budget Start
1988-01-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Krushkal, J; Bat, O; Gigli, I (2000) Evolutionary relationships among proteins encoded by the regulator of complement activation gene cluster. Mol Biol Evol 17:1718-30
Krushkal, J; Kemper, C; Gigli, I (1998) Ancient origin of human complement factor H. J Mol Evol 47:625-30
Zipfel, P F; Kemper, C; Dahmen, A et al. (1996) Cloning and recombinant expression of a barred sand bass (Paralabrax nebulifer) cDNA. The encoded protein displays structural homology and immunological crossreactivity to human complement/cofactor related plasma proteins. Dev Comp Immunol 20:407-16
Dahmen, A; Kaidoh, T; Zipfel, P F et al. (1994) Cloning and characterization of a cDNA representing a putative complement-regulatory plasma protein from barred sand bass (Parablax neblifer). Biochem J 301 ( Pt 2):391-7
Barrett, K E; Yen, A; Bigby, T D et al. (1994) Inhibition of human peripheral blood lymphocyte function by protoporphyrin and longwave ultraviolet light. J Immunol 153:3286-94
Dovezenski, N; Billetta, R; Gigli, I (1992) Expression and localization of proteins of the complement system in human skin. J Clin Invest 90:2000-12
Tausk, F; Gigli, I (1990) The human C3b receptor: function and role in human diseases. J Invest Dermatol 94:141S-145S
Reed, S L; Gigli, I (1990) Lysis of complement-sensitive Entamoeba histolytica by activated terminal complement components. Initiation of complement activation by an extracellular neutral cysteine proteinase. J Clin Invest 86:1815-22
Kaidoh, T; Gigli, I (1989) Phylogeny of the plasma regulatory proteins of the complement system. Prog Clin Biol Res 297:199-209
Reed, S L; Keene, W E; McKerrow, J H et al. (1989) Cleavage of C3 by a neutral cysteine proteinase of Entamoeba histolytica. J Immunol 143:189-95

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