Anti-DNA autoreactivity in C4-deficient mice

Abstract

Mice lacking the classical complement component C4 (C4(-/-)) were evaluated for autoreactivity because classical complement deficiencies are major risk factors for human systemic lupus erythematosus (SLE). Naive, 6-month-old C4(-/-) mice have significantly more IgM anti-double-strand DNA antibodies than C4(+/+) controls. By 9 months, IgG anti-dsDNA antibodies are increased and this spontaneous autoreactivity is evident across a mixture of genetic backgrounds. C4(+/-) heterozygous mice also develop autoantibodies, reminiscent of the high incidence of partial C4 deficiency observed in human SLE. Kidneys of C4(-/-) mice have glomerular immune complexes, but progressive renal disease is not apparent in unmanipulated animals. Nonetheless, splenic B cells from C4(-/-) and not C4(+/+) mice as young as 3 months can be triggered to secrete IgM anti-dsDNA antibodies in vitro, before autoantibody titers are significantly elevated in vivo. These findings suggest that C4 normally helps prevent early stages of autoimmune disease and that C4 deficiency predisposes to abnormal regulation of autoreactive B cells.