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


CONCLUSIONS
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.
Yoshida
Hideo
H
Department of Medicine, University of Florida, Gainesville, FL 32610-0221, USA.
Satoh
Minoru
M
Behney
Krista M
KM
Lee
Chee-Gun
CG
Richards
Hanno B
HB
Shaheen
Victoria M
VM
Yang
Jun-Qi
JQ
Singh
Ram R
RR
Reeves
Westley H
WH
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001202:Ascitic Fluid / Q000166:cytology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008136:Longevity / Q000187:drug effects; D008181:Lupus Nephritis / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D011507:Proteinuria / Q000652:urine; D020365:RNA Helicases / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000008:administration & dosage / Q000633:toxicity*
D000974:Antibodies, Antinuclear; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D013729:Terpenes; C009042:pristane; D020365:RNA Helicases