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 co ntrast, inherited deficiency of classical pathway components, particul arly Clq (ref, 1), is powerfully associated with the development of SL E, This leads to the hypothesis that a physiological action of the ear ly part of the classical pathway protects against the development of S LE (ref, 2) and implies that Clq may play a key role in this respect. Clq-deficient (C1qa(-/-)) mice were generated by gene targeting and mo nitored for eight months. C1qa(-/-) mice had increased mortality and h igher titres of autoantibodies, compared with strain-matched controls. Of the C1qa(-/-) mice, 25% had glomerulonephritis with immune deposit s and multiple apoptotic cell bodies. Among mice without glomeruloneph ritis, there were significantly greater numbers of glomerular apoptoti c bodies in Clq-deficient mice compared with controls. The phenotype a ssociated with Clq deficiency was modified by background genes. These findings are compatible with the hypothesis that Clq deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.