This study examined the interactions between exogenous and endogenous factors shaping the phenotype of lupus in autoimmune (NZB × NZW)F₁ mice exposed to pristane, a model environmental trigger.

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).

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.

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.