Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Abstract

The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

Mesangial cell complement receptor 1‐related protein y limits complement‐dependent neutrophil accumulation in immune complex glomerulonephritis

“…This has been shown by studies of nephrotoxic serum nephritis in DAF −/− Crry −/− C3 +/− mice (i.e. deficient in both DAF and Crry) and our studies with immune complex‐mediated GN in DAF −/− mice 22,30 . In the former setting of Ab‐directed complement activation in the glomerular capillary wall, mice have exacerbated proteinuria, yet comparable C3 deposition and glomerular pathology between DAF −/− Crry −/− C3 +/− and control DAF −/− Crry +/− C3 +/− mice 22 .…”

“…deficient in both DAF and Crry) and our studies with immune complex-mediated GN in DAF )/) mice. 22,30 In the former setting of Ab-directed complement activation in the glomerular capillary wall, mice have exacerbated proteinuria, yet comparable C3 deposition and glomerular pathology between DAF )/) Crry )/) C3 +/) and control DAF )/) Crry +/) C3 +/) mice. 22 The finding that there is little overlap in the sites of complement activation clearly shows that, in addition to differences in specific complement regulatory functions, the distributions of the C3 regulators have substantial effects on where complement can be activated and on the resultant disease expression within the kidney.…”

Expression of CD55, CD59, and CD35 on red blood cells of β-thalassaemia patients

“…showed decreased CD55 and CD59 expression on RBCs of SLE patients with nephritis [13]. DAF deficiency led to a significantly increased incidence of proliferative glomerulonephritis [20]. The CD35/CR1 for C3b of erythrocytes has already been shown to bind complement-activating bacteria, viruses, and immune complexes, and deliver immune complexes to the fixed macrophages of liver and spleen [10].…”

Complement Regulation in Renal Disease Models

“…78 In comparable studies to examine potential roles for DAF and CD59, both DAF −/− and DAF −/− CD59 −/− mice had significantly increased glomerular C3 deposition which correlated with development of GN relative to wildtype controls. 79 There were no histological or functional disease features in CD59 −/− or wildtype mice with CSS, which is indirect evidence that C5b-9 has a limited role in this model.…”