Protection and injury: the differing roles of complement in the development of glomerular injury.
The role of complement in autoimmune glomerulonephritis (as in other autoimmune diseases) is paradoxical, in that complement activation mediates acute inflammatory injury, yet inherited deficiency of complement may predispose to immune complex disease in particular immune complex glomerulonephritis. We have investigated the role of complement in experimentally induced glomerulonephritis in C3-deficient mice, using antibodies against the mouse glomerular basement membrane (GBM). In the acute phase of the disease, which is initiated by binding of heterologous antibody to the GBM, we confirmed that the inflammatory injury was positively complement dependent, with C3-deficient mice developing less severe injury. In contrast, in the autologous phase of the disease, mediated by the immune response against the heterologous antibody fixed in the GBM, the disease was negatively complement dependent. That is, by 14 days after disease induction the C3-deficient mice had heavier proteinuria and more severe uremia (p < 0.001) compared to the complement sufficient mice. The C3-deficient mice also showed a greater accumulation of electron-dense deposits in the GBM. These findings were reproduced in an accelerated model of this disease in which C3-deficient mice also develop more severe functional disturbance and demonstrate a higher rate of immune complex deposition. These data illustrate the potential for the net effect of complement to switch from a detrimental to a protective mode at different stages of autoimmune injury.
Sheerin
N S
NS
Department of Nephrology and Transplantation, Guy's Hospital, Kings College London, London, GB.
Springall
T
T
Abe
K
K
Sacks
S H
SH
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology* / Q000652:urine; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology; D017209:Apoptosis; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D007074:Immunoglobulin G / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011507:Proteinuria / Q000473:pathology; D012709:Serum Albumin / Q000378:metabolism; D014511:Uremia / Q000473:pathology
D000906:Antibodies; D000936:Antigen-Antibody Complex; D003176:Complement C3; D007074:Immunoglobulin G; D012709:Serum Albumin