Complement C4 Inhibits Systemic Autoimmunity through a Mechanism Independent of Complement Receptors CR1 and CR2

doi:10.1084/jem.192.9.1339

Published online 6 November 2000.

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© The Rockefeller University Press, 0022-1007/2000/11/1339/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 9, November 6, 2000 1339-1352

Original Article

Complement C4 Inhibits Systemic Autoimmunity through a Mechanism Independent of Complement Receptors CR1 and CR2

Zhibin Chen^a, Sergei B. Koralov^a, and Garnett Kelsoe^a
^a Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710

Correspondence to: Garnett Kelsoe, Dept. of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710. Tel:919-613-7936 Fax:919-613-7878

The complement system enhances antibody responses to T-dependentantigens, but paradoxically, deficiencies in C1 and C4 are stronglylinked to autoantibody production in humans. In mice, disruptionof the C1qa gene also results in spontaneous autoimmunity. Moreover,deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2)lead to reduced selection against autoreactive B cells and impairedhumoral responses. These observations suggest that C1 and C4act through CR1/CR2 to enhance humoral immunity and somehowsuppress autoimmunity. Here we report high titers of spontaneousantinuclear antibody (ANA) in C4^-/- mice. This systemic lupuserythematosus–like autoimmunity is highly penetrant; by10 mo of age, all C4^-^/- females and most males produced ANA.In contrast, titers and frequencies of ANA in Cr2^-^/- mice, whichare deficient in CR1 and CR2, never rose significantly abovethose in normal controls. Glomerular deposition of immune complexes(ICs), glomerulonephritis, and splenomegaly were observed inC4^-^/- but not Cr2^-^/- mice. C4^-^/-, but not Cr2^-^/-, mice accumulateactivated T and B cells. Clearance of circulating ICs is impairedin preautoimmune C4^-^/-, but not Cr2^-^/-, mice. C4 deficiencycauses spontaneous, lupus-like autoimmunity through a mechanismthat is independent of CR1/CR2.

Key Words: complement, autoantibody, glomerulonephritis, splenomegaly,immune complex

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