title: Fas and Fas ligand mutations inhibit autoantibody production in pristane-induced lupus.
abstract: 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.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: M
authors.initials: M
authors.lastname: Satoh
authors.forename: J P
authors.initials: JP
authors.lastname: Weintraub
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: V M
authors.initials: VM
authors.lastname: Shaheen
authors.forename: H B
authors.initials: HB
authors.lastname: Richards
authors.forename: M
authors.initials: M
authors.lastname: Shaw
authors.forename: W H
authors.initials: WH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D005260:Female; D007108:Immune Tolerance / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007136:Immunoglobulins / Q000096:biosynthesis / Q000097:blood; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008024:Ligands; D008181:Lupus Nephritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D009154:Mutation; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced; D017411:Ribonucleoproteins, Small Nuclear; D013045:Species Specificity; D016019:Survival Analysis; D013729:Terpenes / Q000633:toxicity*; D019014:fas Receptor / Q000235:genetics*; D055517:snRNP Core Proteins
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D002843:Chromatin; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D017411:Ribonucleoproteins, Small Nuclear; D013729:Terpenes; D019014:fas Receptor; D055517:snRNP Core Proteins; C009042:pristane