The proposed research will be performed in a guinea pig model of experimental autoimmune glomerulonephritis in which animals with deposits of autologous antibody to glomerular basement membrane (GBM) develop sustained heavy proteinuria. In most proteinuric animals, anti-GBM antibody deposits are not accompanied by deposits of B1C-B1A (C3) in Vivo, and circulating deposited and eluted anti-GBM antibody does not fix C3 in vitro. The focal, non-inflammatory histologic lesion in proteinuric animals is accompanied by a diffuse decrease in staining for glomerular sialoprotein and a unique, electron-lucent ultrastructural GBM lesion. The studies proposed will further define the immunopathogenesis of this apparently complement-independent glomerular lesion and investigate how this immunologic mechanism mediates alterations in glomerular permeability by: 1. Using eluted antibody to a) transfer the lesion to normal recipients, and b) evaluate the role of complement in mediating glomerular injury using recipients depleted of, or deficient in, selected complement components and neutrophiles. Active immunization of C4 deficient animals will also be carried out. 2. Establishing the role of the morphologic GBM lesion in altering GBM permeability using electron-dense tracer molecules. 3. Contrasting this lesion to that mediated by complement-dependent nephrotoxic antibody. 4. Defining the sequence in which anti-GBM antibody of the gamma 1 and gamma 2 subclasses deposit, sialoprotein alterations occur, ultrastructural GBM lesions appear and the GBM becomes permeable to various serum proteins, and 5. Investigating whether antibody induces GBM damage in this model directly or as a consequence of interference with epithelial cell function causing secondary changes in GBM structure and function. BIBLIOGRAPHIC REFERENCES: Couser W.G., Stilmant M.M. and Darby C: Autologous immune complex nephropathy. I. Sequential study of immune complex deposition, ultrastructural changes, proteinuria and alterations in glomerular sialoprotein. Lab. Invest. 34:23-30, 1976. Couser W.G. and Stilmant M.M.: Immunopathology of the aging rat kidney. J. Gerontology. 31: 13-22, 1976.