J. Exp. Med., Volume 188, Number 5, September 7, 1998 985-990

Interleukin 6 Dependence of Anti-DNA Antibody Production: Evidence for Two Pathways of Autoantibody Formation in Pristane-induced Lupus

By Hanno B. Richards,^* Minoru Satoh,^* Melody Shaw,^* Claude Libert, Valeria Poli, and Westley H. Reeves^*

From the ^* Department of Medicine and the Department of Microbiology/Immunology, Thurston Arthritis Research Center, and University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599-7280; and the  Istituto di Ricerche di Biologia Molecolare, P. Angeletti, 00040 Pomezia, Italy

Pristane induces a lupus-like syndrome in nonautoimmune mice characterized by the development of glomerulonephritis and lupus-associated autoantibodies. This is accompanied by overproduction of interleukin (IL)-6, a cytokine linked with autoimmune phenomena. The goal of this study was to evaluate the role of IL-6 in autoantibody production in pristane-induced lupus. BALB/cAn IL-6-deficient (/) and -intact (+/+) mice were treated with pristane or phosphate-buffered saline, and autoantibody production was evaluated. Pristane induced high levels of immunoglobulin (Ig)G anti-single-stranded DNA, -double-stranded (ds)DNA, and -chromatin antibodies in IL-6^+/+, but not IL-6^/ mice by enzyme-linked immunosorbent assay. High titer IgG anti-dsDNA antibodies also were detected in sera from +/+, but not /, mice by Crithidia luciliae kinetoplast staining. The onset of IgG anti-dsDNA antibody production in +/+ mice occurred >5 mo after pristane treatment, well after the onset of nephritis, suggesting that these antibodies are not directly responsible for inducing renal disease. In contrast to anti-DNA, the frequencies of anti-nRNP/Sm and anti-Su antibodies were similar in pristane-treated IL-6^/ and IL-6^+/+ mice. However, levels were higher in the +/+ group. These results suggest that IgG anti-DNA and chromatin antibodies in pristane-treated mice are strictly IL-6 dependent, whereas induction of anti-nRNP/Sm and Su autoantibodies is IL-6 independent. The IL-6 dependence of anti-DNA, but not anti-nRNP/Sm, may have implications for understanding the patterns of autoantibody production in lupus. Anti-DNA antibodies are produced transiently, mainly during periods of disease activity, whereas anti-nRNP/Sm antibody levels are relatively insensitive to disease activity. This may reflect the differential IL-6 dependence of the two responses.

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