The contribution of antibody-mediated cytotoxicity and immune-complex formation to tubulointerstitial disease in passive Heymann nephritis.

Passive Heymann nephritis (PHN), an experimental model of membranous nephropathy, is produced by Fx1A antiserum, which also reacts with antigens on the brush border (gp 330) and basolateral membrane (gp 90) of proximal tubules. We examined tubulointerstitial disease in PHN, identifying two distinct processes occurring on the luminal and basolateral membranes, respectively. Injected antibody bound diffusely to the tubular brush border from Day 1 to Day 7, followed by sloughing of microvilli and tubular-cell regeneration. Fine granular deposits of Fx1A antibody were present along the basolateral cell membrane by Day 1. These deposits rearranged in situ, enlarged, and became more focally distributed along tubular basement membranes (TBM). Interstitial inflammation, dominated by macrophages (Ia+, ED-1+) in association with a smaller number of T-cytotoxic cells (OX19+, OX8+) began by Day 3, reached peak intensity and persisted throughout the autologous phase (to Day 21). The distribution of focal clusters of interstitial macrophages predominately in association with TBM-immune deposits was demonstrated. Complement depletion prevented proteinuria but TBM deposits developed and the interstitial inflammation was unchanged. All aspects of the tubulointerstitial disease were amplified by a second injection of Fx1A antiserum. In vitro, Fx1A antibody bound to the surface of isolated proximal tubular epithelial cells and redistributed to form clusters of immune aggregates. Anti-Fx1A-induced cytotoxicity of tubular cells was demonstrated by prelabeling cells with 2'-7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. The degree of cytotoxicity was dependent on complement concentration and the duration of incubation at 37 degrees C. PHN induced by Fx1A antiserum causes tubular-cell injury following interactions with brush-border antigens and TBM immune-complex disease associated with interstitial inflammation. These findings may be relevant to the acute and chronic interstitial disease of human membranous nephropathy.