Effect of an exogenous trigger on the pathogenesis of lupus in (NZB x NZW)F1 mice

Arthritis Rheum. 2002 Aug;46(8):2235-44. doi: 10.1002/art.10441.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Antinuclear / analysis
  • Ascitic Fluid / cytology
  • Ascitic Fluid / metabolism
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Predisposition to Disease*
  • Immunoglobulin G / analysis
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / toxicity*
  • Injections, Intraperitoneal
  • Longevity / drug effects
  • Lupus Nephritis / etiology*
  • Lupus Nephritis / metabolism
  • Mice
  • Mice, Inbred NZB
  • Proteinuria / urine
  • RNA Helicases / immunology
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / metabolism
  • Terpenes / administration & dosage
  • Terpenes / toxicity*


  • Antibodies, Antinuclear
  • Cytokines
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Terpenes
  • pristane
  • RNA Helicases