Anti-glomerular basement membrane antibody-induced experimental glomerulonephritis: evidence for dose-dependent, direct antibody and complement-induced, cell-independent injury.

Abstract

The immunopathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) involves the triad of antibody fixation to the glomerular basement membrane, local complement activation and polymorphonuclear leucocyte (PMN) infiltration. We sought to investigate the potential for contributions to renal injury from each component of this triad (i.e., antibody, complement, and PMN). This study compares the ability of antibody to induce injury in normal, PMN-depleted and dual (i.e., PMN + complement)-depleted rabbits by assessing the quantity of kidney-fixed antibody (KFA) necessary to induce proteinuria. (The KFA levels are expressed in micrograms of antibody bound per gram renal cortex.) Normal animals developed significant proteinuria at KFA 60 +/- 6 micrograms/g. PMN-depleted animals were injury free at KFA 60 +/- 6 micrograms/g, but developed heavy proteinuria at KFA 140 +/- 5 micrograms/g. The protection from injury by PMN depletion at lower KFA levels confirms the important contribution of PMN to injury in this model. Furthermore, the demonstration of a clearcut threshold for injury despite PMN-depletion indicates that glomerular antibody deposition and complement activation can cause direct PMN-independent injury. Dual depletion studies showed a significantly higher KFA threshold for injury in PMN + complement-depleted animals than in PMN-depleted, complement intact animals (195 +/- 10 micrograms/g, cf. 140 +/- 5 micrograms/g; p less than 0.01). The occurrence of injury despite dual mediator depletion demonstrates that antibody itself can produce direct, complement and PMN independent renal injury. Together the PMN depletion and dual depletion studies indicate that antibody-induced glomerular complement activation produces direct, PMN-independent renal injury that can be prevented by complement depletion. Thus each of the potential mediators studied is individually capable of producing renal injury in anti-GBM-GN. In addition to the well established injurious role of PMN, this study demonstrates that glomerular complement activation and anti-GBM antibody deposition may both produce neutrophil-independent components of renal injury. The relative contributions of the individual mediators to injury is dependent on the quantity of antibody deposited within the glomerulus.