Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.
The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.
Botto
M
M
Rheumatology Section, Hammersmith Campus, Imperial College School of Medicine, London, UK.
Dell'Agnola
C
C
Bygrave
A E
AE
Thompson
E M
EM
Cook
H T
HT
Petry
F
F
Loos
M
M
Pandolfi
P P
PP
Walport
M J
MJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015922:Complement C1q / Q000172:deficiency* / Q000235:genetics; D003433:Crosses, Genetic; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D015922:Complement C1q