To understand mechanisms of injury by antibodies and antigen-antibodies complexes, we will examine how the interaction of antibodies with cell surface antigens causes cell and tissue injury in experimental models """"""""in vivo"""""""" and """"""""in vitro"""""""". Our recent results have indicated that the interaction of antibodies with cell surface antigens """"""""in vivo"""""""" is governed by mechanisms similar to those described in """"""""in vitro"""""""" systems when soluble ligands combine with plasma membrane antigens or receptors. The consequences of the interaction of certain cell surface antigens with their antibodies for the cells on which it is occurring, the tissues of which they are part, and more remote tissues, are the subject of the inquiry. We will examine four physically or conceptually related immunological systems: angiotensin converting enzyme and thrombomodulin in rat and rabbit endothelium; Forssman antigen and thrombomodulin in guinea pig endothelium; and Heymann-like antigens in human glomerular epithelium. We will determine the response of cultured endothelial cells to the binding of antibody by examining short - and long-term effects of antigen redistribution, co-redistribution, complement fixation, and the role of cytokines and pharmacologic agents, as well as the effect of antigen redistribution on endothelial structures and functions. We will also examine antibody-cell surface antigen interactions in isolated perfused lungs and kidneys and in living animals, especially the consequences of immunologic shedding of endothelial anti-antibody complexes in the circulation. Shedding of """"""""bystander"""""""" immunologically unrelated antigens, sharing plasma membrane domains with the immunologically-shed antigen, and the development of resistance to antibody-mediated injury through antigenic modulation will also be analyzed. In an extension of these studies we will test the hypothesis that human idiopathic membranous glomerulonephritis results from interaction of antibodies with antigens expressed at the surface of glomerular visceral epithelial cells. The experimental models available or developed in our laboratory provide the tools for this proposal, using morphological, functional, serological and quantitative methods. The ultimate aim is to advance our knowledge on how interaction of antibodies with cell surface antigens induces injury in tissues, thus contributing to a better understanding of graft rejection and adaptation and of human idiopathic membranous glomerulonephritis.
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