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Fas and Fas Ligand Mutations Inhibit Autoantibody Production in Pristane-Induced Lupus¹

Minoru Satoh^*, Jory P. Weintraub, Hideo Yoshida^*, Victoria M. Shaheen, Hanno B. Richards^*, Melody Shaw and Westley H. Reeves^2,*

^* Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL 32610; and Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599

Mutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.

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