Objective:
This study examined the interactions between exogenous and endogenous factors shaping the phenotype of lupus in autoimmune (nzb x nzw)f(1) mice exposed to pristane, a model environmental trigger.
Methods:
Frequencies of various autoantibodies in untreated nzb/nzw mice were determined by various means (immunoprecipitation, enzyme-linked immunosorbent assay [elisa], crithidia luciliae kinetoplast staining). pristane or saline was administered intraperitoneally to 9-12-week-old nzb/nzw mice, followed by serial studies of autoantibodies, total ig levels (elisa), and proteinuria (dipstick).
Results:
Besides antichromatin/dna responses, nzb/nzw mice spontaneously produced novel autoantibodies against the double-stranded rna binding protein rna helicase a (rha). in contrast, nzb/nzw mice (n = 70) did not produce autoantibodies against the nuclear rnp (nrnp), sm, ro, or la antigens. pristane exposure synergistically activated the production of antichromatin/dna antibodies and dramatically accelerated renal disease. production of anti-nrnp/sm and su autoantibodies also was induced, indicating that the unresponsiveness of nzb/nzw mice to these antigens can be overcome. curiously, pristane treatment did not enhance the production of anti-rha, suggesting that these autoantibodies are regulated differently than anti-dna/chromatin and sm. in contrast to previous reports that suggest a critical role of deficient interleukin-12 (il-12) production in the pathogenesis of lupus, there was overproduction of il-12 in the peritoneal cavity of pristane-treated nzb/nzw mice, and their spleen cells also produced large amounts of il-12.
Conclusion:
These data lead us to propose that environmental influences exacerbate autoimmune manifestations in genetically lupus-susceptible mice through their stimulatory effects on proinflammatory cytokines, such as il-12.