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
Dept. of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710.919-613-7878919-613-7936

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 systemiclupus erythematosus–like autoimmunity is highly penetrant;by 10 mo of age, all C4^–^/– females and most malesproduced ANA. In contrast, titers and frequencies of ANA inCr2^–^/– mice, which are deficient in CR1 and CR2,never rose significantly above those in normal controls. Glomerulardeposition of immune complexes (ICs), glomerulonephritis, andsplenomegaly were observed in C4^–^/– 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 deficiency causes spontaneous, lupus-like autoimmunitythrough a mechanism that is independent of CR1/CR2.

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

Abbreviations used in this paper: ANAs, antinuclear antibodies;BCR, B cell antigen receptor; BUN, blood urea nitrogen; GC,germinal center; HRP, horseradish peroxidase; ICs, immune complexes;RU, relative unit; SLE, systemic lupus erythematosus.

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