The overall objective of this proposal is to examine the fundamental question as to how and why immune complexes localize in the glomerulus.
The specific aims will be to determine the relative contributions of several physicochemical properties of immune complexes or their components to the pattern and severity of glomerulonephritis. The pathogenic effects of preformed immune complexes will be systematically compared to the effects of administering individual immune complex components to Sprague-Dawley rats. The clarification of the relative importance of preformed immune complexes or locally (in situ) assembled immune complexes to glomerular injury will be a central issue of this proposal and may prove to be essential to the development of effective treatment strategies for glomerulonephritis. The methodology to achieve this goal will employ: 1) immunopathologic and physiological studies of animals injected with free antigen or antibody, or covalently crosslinked immune complexes of varying net charge, electron density, and molecular size; 2) in vitro studies comparing complement activation as induced by preformed immune complexes to that induced by individual antigen and antibody components interacting separately with complement; 3) studies to determine the role of the physicochemical properties of antibody avidity and antibody charge in the pathogenesis of glomerulonephritis; and 4) kinetic studies of the mesangial clearance of anionic or cationic macroaggregates in an effort to determine if the physicochemical property of electrical charge alters mesangial function. It is the hope of the applicant that these studies will help achieve a more integrated understanding of how immune complexes or their individual antigen-antibody components determine the pattern and severity of glomerular injury.
