The long-term objective of this research project is to obtain experimental information that will lead to a thorough understanding of the role of antibody/dsDNA immune complexes in the pathogenesis of systemic lupus erythematous (SLE). Several lines of evidence indicate that the potential of immune complexes to be safely cleared from the circulation may depend upon their ability to fix complement and be recognized by the C3b/C4b receptors of human red blood cells. More recent evidence suggests that a similar mechanism may operate in non-primates, but in this case the relevant receptors are apparently on the animals' platelets, rather than red blood cells. In vivo studies on baboons, guinea pigs and rabbits will therefore focus on how the physical properties of the antibody/dsDNA immune complexes and the complement activity and C3b/C4b receptor activity of the animals affect the clearance of these immune complexes from the circulation. Specifically, we intend to do the following: (1) Investigate the rate of clearance of radiolabeled antibody/DNA immune complexes of different sizes from the circulation of these animals. (2) Determine the organ distribution of the complexes after they leave the circulation. (3) Examine how compromising the complement system of the animals influences the immune complex clearance rates and organ distribution. (4) Perform in vitro studies to quantitate C3 fragments and antibody/dsDNA stoichiometries on these complexes and correlate these results with the in vivo findings. These studies will be conducted on immune complexes prepared with both dsDNA and ss DNA molecules in a wide range of molecular weights. Principal techniques to be used include radioimmunoassays, centrifugation, and a variety of methods that focus on complement technology. Information gained from the successful completion of the proposed research will add to our knowledge of immune complex diseases and should help in the design of specific therapeutic modalities for such diseases.
