ANTIGLOMERULAR BASEMENT MEMBRANE NEPHRITIS IN BEIGE MICE Deficiency of Leukocytic Neutral Proteinases Prevents the Induction of Albuminuria in the Heterologous Phase BY GIDEON SCHRIJVER, JOOST SCHALKWIJK,*

Theglomerular damage during the early phase ofthe passive antiglomerular basement membrane (GBM)' nephritis, a well-known model of experimental renal disease, is dependent on complement and polymorphonuclear granulocytes (PMN) in most animal species studied (1-3) . Recently we have described a murine model of anti-GBM nephritis, in which the massive albuminuria occurring after the injection ofheterologous antibody is not mediated by complement, but is completely dependent on the presence of PMN in the glomeruli (4). Lysosomal proteinases and reactive oxygen metabolites (ROM) from activated PMN, acting either alone or synergistically, have been implicated as agents contributing to the glomerular injury and enhanced permeability for proteins (5-12) . Activated PMN secrete lysosomal enzymes, especially when they are firmly attached to extracellular matrices (8-10, 13, 14). It has been established that neutral proteinases are major factors in tissue destruction at sites of inflammation . These enzymes can cleave many if not all of the constituents of the extracellular matrix, includingthe GBM(13-17) . Not only lysosomal proteinases but also ROM, generated during a respiratory burst from activated PMN, can function as mediators of tissue injury (16, 18, 19). Several in vitro and in vivo studies have reported the participation of ROM in neutrophil-dependent glomerular disease (6, 7, 11, 12, 17). ROM have been shown to degrade GBM in vitro in concert with lysosomal proteinases, although others could not confirm this synergistic effect (20-22) . In most experiments the evidence of their mediator function of glomerular injury is largely derived from the inhibitory effects of ROM scavengers on the damage produced by PMN (5-7, 17, 23). To examine more precisely the role of leukocytic neutral proteinases, we induced an anti-GBM nephritis in C57BL/6J,bg/bg (beige) mice with a genetic defect analogous to the Chediak-Higashi syndrome in man, in which PMN are reported to be deficient for elastase and cathepsin G (24, 25). The severe albuminuria after injec-