The major objective of the proposed experiments is to clarify mechanisms of tissue injury which result from deposition of antigen-antibody complexes. Systemic lupus erythematosus (SLE) is a prototype model for the study of immune complex disease in man. Antigen-antibody complexes derived from the circulation as well as complexes formed in situ appear to be of pathogenetic importance. Prior studies indicate that the polynucleotide-anti-polynucleotide system is of primary importance. To further define these complexes, the specificity and relative antigen avidity of anti-polynucleotide antibodies will be studied, and polynucleotide backbone epitopes will be defined. The cytotoxic potential of in situ complexes formed between DNA denatured by UV light or damaged cell nuclei and anti-polynucleotide antibodies will be evaluated. Studies concerning the role of autoantibodies to glomerular and cutaneous basement membrane will be continued to assess the contribution of auto-immune reactions in SLE and related diseases. The complement system mediates inflammatory lesions, following activation of Clg-globulin, by a series of enzyme reactions which modulate formation of peptide fragments, intermediate complexes and the membrane attack complex (MAC). Ultrastructural localization of the MAC and immunochemical studies of neoantigen determinants will be performed to characterize terminal complement complexes, factors which initiate classical or alternative pathway activation and the pathogenetic importance of membranolysis. Depletion of terminal complement components in experimental immune disease to inhibit assembly of the MAC is also planned to determine if the failure to form this complex affects inflammation and membrane injury. The following reagents and techniques will be utilized for the performance of these studies: monoclonal antibodies to polynucleotides and complement proteins; rabbit antisera; immunofluorescence; immunoelectron microscopy; hemolytic complement assays; and solid phase enzyme immuno-assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR021715-11
Application #
3155213
Study Section
Experimental Immunology Study Section (EI)
Project Start
1975-01-01
Project End
1989-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Hahnemann University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129